Complex and Multidimensional Lipid Raft Alterations in a Murine Model of Alzheimer's Disease

Abstract

Various animal models of Alzheimer's disease (AD) have been created to assist our appreciation of AD pathophysiology, as well as aid development of novel therapeutic strategies. Despite the discovery of mutated proteins that predict the development of AD, there are likely to be many other proteins also involved in this disorder. Complex physiological processes are mediated by coherent interactions of clusters of functionally related proteins. Synaptic dysfunction is one of the hallmarks of AD. Synaptic proteins are organized into multiprotein complexes in high-density membrane structures, known as lipid rafts. These microdomains enable coherent clustering of synergistic signaling proteins. We have used mass analytical techniques and multiple bioinformatic approaches to better appreciate the intricate interactions of these multifunctional proteins in the 3xTgAD murine model of AD. Our results show that there are significant alterations in numerous receptor/cell signaling proteins in cortical lipid rafts isolated from 3xTgAD mice.

1. Introduction

Alzheimer’s disease (AD) is one of the most prevalent neurodegenerative disorders amongst adults of advanced age, and it is the most common form of dementia and cognitive impairment [1, 2]. The behavioral abnormalities in AD result from dysfunction and death of neurons in brain regions involved in cognition and mood, such as the hippocampus, amygdala, and cortical regions. Progressive short-term and eventual long-term memory loss and reduced cognitive capacity are associated with two primary neurodegenerative lesions, that is, extra- and intracellular β-amyloid plaques, as well as neurofibrillary tangles (NFTs) composed of the microtubule protein tau [3–5]. In addition to the effects of amyloid plaques and NFTs, the lipid trafficking molecule, apolipoprotein E4 (apoE4), has also been demonstrated to be a genetic risk factor for AD [6, 7]. The AD characteristic extracellular plaques, found in both the hippocampus and cortex of AD patients, consist of 39–42 amino acid long amyloid-β (Aβ) peptides. These extracellular peptides are generated by digestion of a transmembrane amyloid precursor protein (APP). Proteolysis of the transmembrane APP by a set of intramembrane enzymes, β- (also known as BACE-1) and γ-secretases, is thought to be responsible for toxic Aβ creation [5]. The discovery of familial mutations in the APP gene that were strongly correlated with the presentation of AD reinforced the importance of Aβ processing in this disorder. A growing body of evidence indicates that changes in lipid and cholesterol homeostasis can influence AD progression and specifically Aβ production. One of the prime sub cellular regions of amyloidogenic APP processing is thought to be cholesterol-enriched membrane microdomains, termed lipid rafts [8]. Cellular organization of protein signaling complexes, to enhance the magnitude and fidelity of transmembrane signaling receptors, is facilitated by variations in the lipid constituents of the plasma membrane. Lipid rafts represent discontinuous regions of the plasma membrane that form functional microdomains, which constrain the association of proteins in a coherent and advantageous manner with respect to neurotransmissive signaling [9]. Disruption of the correct stoichiometry of signaling complexes within lipid rafts may underpin the etiology of many different neurodegenerative disorders [10–12]. The hypothesis that changes in the lipid composition of rafts contribute to AD pathology has gained considerable support. For example, ApoE4 has been strongly correlated with the generation of AD symptomatology. Both of the amyloidogenic processing enzymes (β- and γ-secretase), as well as APP, are all enriched in lipid raft membranes [13, 14]. Reinforcing the connection between lipid density levels and Aβ production, increasing cholesterol levels elevate the activity of both β-secretase (BACE-1) and γ-secretase [14, 15]. In addition, ganglioside lipids, which are also enriched in lipid rafts, can control the assembly of amyloid-β proteins [16, 17]. Changes in ganglioside composition, similar to those noted in human AD patients, are also observed in different transgenic mouse models of AD [18]. In addition to a role of the lipid components of lipid rafts in controlling amyloidogenesis, these raft environments may also affect NFTs as well. It has been demonstrated that Aβ can induce activation of the tyrosine kinase Fyn in neuronal cells, that is then recruited to lipid rafts which catalyzes phosphorylation of tyrosine residue 18 on tau [19, 20]. Association of Aβ plaques to lipid rafts can mediate recruitment of excess Fyn to the rafts, as well as further recruitment and phosphorylation of tau. These activities are thought to induce neurotoxicity via the effects of tau-induced changes in the actin cytoskeleton and receptor/cellular signaling pathways [21]. Therefore, the potential changes in the lipid composition of lipid rafts, caused by exposure to cytotoxic activities characteristic to AD, can induce profound changes in cellular signal transduction and thereby induce intracellular changes that lead to the development of AD. The complexity of protein complexes within the lipid raft environments raises considerable challenges to understanding the molecular mechanisms of AD pathophysiology in both the hippocampus and cortex of animals. Therefore, we have employed a shotgun proteomics approach, allied to advanced bioinformatic functional profiling, to gain a broad and detailed appreciation of the alterations in signaling proteins in lipid rafts in the triple-transgenic (3xTgAD) model of AD [22]. Our study demonstrates that cortical lipid rafts are profoundly affected in the 3xTgAD mice and that many of the neurophysiological deficits characteristic of AD (impaired synaptic strength, impaired learning and memory, and increased oxidative stress) can be strongly linked to changes in receptor and cell signaling events in the lipid rafts in these animals. Therefore, the lipid raft environments can be seen as one of the most important pathophysiological loci of this disorder.

2. Methods

2.1. Animals and Morris Water Maze Testing

Animal care and experimental procedures followed NIH guidelines and were approved by the National Institute on Aging Animal Care, and Use Committee. Experiments were performed using male 3xTgAD [22–24] and control male C57-BL6 mice that were maintained under a 12-hour light/12-hour dark cycle with continuous access to food and water. Water maze testing took place using a modified version of the methodology described previously [25]. Briefly, animals (𝑛=10 per group, control male C57-BL6 or male 3xTgAD, on a C57-BL6 background) received 8 days of acquisition training using a nonvisible target platform, consisting of four trials per day, with an intertrial interval of approximately 10 minutes. Each trial lasted until the animal found the platform, or for a maximum of 60 seconds; animals that failed to find the platform within 60 seconds were guided there by the experimenter. On each trial, mice were placed into the pool, facing the wall, with start locations varied pseudorandomly. Distance swam to escape the water, escape time, and swim speed were measured for either control or 3xTgAD mice using a HVS2020 automated tracking system (HVS Image, UK).

2.2. Isolation of Lipid Raft Detergent-Resistant Membranes

The mice were anesthetized with isoflurane, decapitated, and the brain was microdissected on ice. After removal of the cortex, the tissue was split into left and right hemisphere, half for mass spectrometry raft analysis and half to prepare lipid raft tissues for Western blot analysis. The hemicortices were washed twice in ice-cold phosphate buffered saline (PBS) and then transferred into a Tris-saline buffer supplemented with a cocktail of protease and phosphatase inhibitors (50 mM Tris-HCl, 150 mM NaCl, 5 mM EDTA, and Roche Complete-Mini (Roche Diagnostics Inc.) protease and phosphatase inhibitor cocktail, pH 7.4). Crude tissue disruption was then rapidly achieved (at 4°C) using a sonic dismembrator (Fisher Scientific Model 100) followed by a brief centrifugation (4°C, 1000 ×g, 10 minutes) to pellet cell nuclei and unbroken cells. The resultant supernatant was removed and Triton X-100 (Sigma Aldrich, USA) was added to the Tris-saline buffer to a final concentration of 1%. The supernatant membranes were then incubated at 4°C for 60 minutes in the Triton X-100 Tris-saline solution. After incubation, the supernatant solution was then added to a discontinuous gradient of 30% and 60% OptiPrep (Iodixanol, Sigma Aldrich, and U.S.A.) before centrifugation at 200 000 ×g for 16 hours at 4°C. After centrifugation, a detergent-resistant lipid band was evident in the vertical solution column. Multiple fractions of 300 μl volumes were then removed from the vertical centrifugation column. Proteins were then extracted from these fractions using a proprietary ProteoExtract (EMD Biosciences) kit, according to the manufacturer’s instructions. Isolated protein pellets were then prepared for mass spectrometric analysis.

2.3. Mass Spectrometric Protein Analysis

Protein pellets were dissolved into an ammonium bicarbonate buffer (100 mM, pH 8.5) and then reduced with dithiothreitol (500 mM: Pierce Biotechnology), alkylated with iodoacetamide (800 mM: Sigma Aldrich) and then digested with modified trypsin (5–10 μg) (Promega) at 37°C for 17 hours. Proteolysis was terminated by the addition of glacial acetic acid. Tryptic peptides were then loaded onto a desalting column (360×200 μm fused silica packed with 15 cm of C18 beads (YMC ODS-AQ, Waters)), washed with 0.1% acetic acid and eluted into sample tubes with 80% acetonitrile in 0.1% acetic acid. Sample volume was reduced to usable volumes under vacuum on a Savant SpeedVac. Samples were then transferred onto a PicoFrit (75×100 mm) column packed with ProteoPep II C₁₈, 300 Å, 5 μm particles (New Objective) connected to a nanoliquid chromatography system (Dionex, Sunnyvale, CA) online with an LTQ ion trap mass spectrometer (Thermo Finnigan, San Jose, CA). The peptides were eluted using a linear gradient of 0–65% acetonitrile over 90 minutes at a flow rate of 250 nl/min directly into the mass spectrometer, which was operated to generate collision-induced dissociation spectra (data-dependent MS/MS mode). The resultant tandem mass spectrometry data were processed using the BioWorks suite, and multiple collected spectra were used to interrogate the NCBI nonredundant mouse and Swiss-Prot protein sequence databases, using the computer algorithm SEQUEST to generate accurate protein identities. Protein genpept accession identities were then converted to Official Gene Symbol terms using NIAID-DAVID v. 6.7 (http://david.abcc.ncifcrf.gov/). The statistical analysis and validation of the search results were performed using MASCOT (Matrix Science). For protein identification, a maximum of three missed tryptic cleavages was used, including fixed modification of carbamidomethylation and variable modifications of oxidized methionine and N-terminal glutamine conversion to pyroglutamic acid in the search. Only proteins with at least two validated peptides and a total score 25 and a confidence of identification of at least 95% were considered valid for reporting. Where required, additional spectral counting was performed to determine simplistic relative quantitation in conjunction with the reported number of identified unambiguous peptides per protein. Three lipid raft fraction samples (fractions 2, 3, and 4) from each three control (nontransgenic gender/age matched C57-BL6) or Alzheimer’s disease (3xTgAD) were pooled and then run in an individual random order. Proteins identified based on two unambiguous peptides that were present in at least two out of the three individual animals were employed for further expression pattern analysis.

2.4. Lipid Raft Band Quantification

Digitized images of centrifugal vertical fluid columns were obtained using a Canon Digital camera and were converted from Joint Photographic Experts Group (JPG) files to a TIFF (Tagged Image File Format) form using L-Process v. 2.2 (image handling software: Fuji-Film). Image densitometry was then performed using Fuji-Film Image Gauge v. 4.2. Lipid raft band intensity was represented as a relative absorbance unit (AU) value with background (B) subtraction per square pixel (px²) (AU-B/px²).

2.5. Western Blotting Procedures

For the examination of specific proteins in cortical cell samples (both lipid raft and nonlipid raft), aliquots were removed from centrifugal fractions from Section 2.2 and their protein concentration was determined with a standard BCA protocol. Aliquot samples for western blotting analysis were then mixed with an equal volume of Laemmli sample buffer [26]. Samples were resolved using one-dimensional gel electrophoresis (SDS-PAGE), followed by electrotransfer to polyvinylenedifluoride (PVDF: PerkinElmer, Waltham, MA). PVDF membranes were blocked for one hour at room temperature in 4% nonfat milk (Santa Cruz; Santa Cruz, CA) before application of specific primary antisera in the same nonfat milk. The presence of primary antibody reactivity with the PVDF membrane was detected by the application of a 1 : 5000 dilution of a species-specific alkaline phosphatase-conjugated secondary antibody (Sigma, St. Louis, MO). PVDF-bound immune complexes of secondary and primary antibodies were subsequently detected using enzyme-linked chemifluorescence (ECF: GE Healthcare; Pittsburgh, PA). Chemifluorescent signals from the membranes were captured and quantified using a Typhoon 9410 phosphorimager (GE Healthcare, Pittsburgh, PA). Specific primary antisera used were obtained from the following sources: flotillin-1, proline-rich tyrosine kinase 2 (Pyk2), focal adhesion kinase (FAK), G protein-coupled receptor kinase interactor-1 (GIT-1), and paxilin antibodies were obtained from BD Bioscience, San Jose, CA; Janus kinase 2 (Jak2), v-Crk avian sarcoma virus CT10 oncogene homolog (Crk), and insulin receptor substrate-1 (IRS1) antibodies were obtained from Santa Cruz Biotechnology Corporation, CA; caspase-7, FKBP12-rapamycin complex-associated protein 1/mammalian target of rapamycin (FRAP1/mTOR), and Fyn and IGF-1 receptor beta antibodies were obtained from Cell Signaling Technology, Danvers, MA); G protein-regulated inducer of neurite outgrowth 2 (Grin2) antibody was obtained from Sigma Aldrich. For the identification of nonspecific total proteins in each sample the highly sensitive protein dye, SYPRO Ruby (Invitrogen Corporation) was employed. Fixed SDS-PAGE gels were immersed in SYPRO-Ruby for 1 hour and then washed in deionized water before scanning using a Typhoon 9410 phosphorimager (GE Healthcare, Pittsburgh, PA).

2.6. Bioinformatic Analyses

Protein identities were converted to standard gene symbol nomenclature for simplicity of usage with the batch conversion tool of NIH Bioinformatics Resources DAVID v. 6.7 (http://david.abcc.ncifcrf.gov/). Primary protein sets (containing consistently identified lipid raft extract proteins) were organized into functional signaling pathway groups and then analyzed for their differential significance of population of these canonical signaling pathways. To compare the relative degree of association of specific signaling pathways with the control or 3xTgAD protein sets, the difference between the signaling pathways “hybrid scores” was calculated (control subtracted from 3xTgAD). The magnitude of the “hybrid score” is indicative of strength and significance of association of the input protein set with the specific signaling pathway. Signaling pathway hybrid scores were generated using a process that takes into account the significant population and potential activation of that pathway by multiplying the pathway enrichment ratio (percentage of proteins in a designated pathway that were also found in the experimental dataset) and the probability (𝑃) that the respective pathway is significantly associated with the experimental dataset. However, to create a simple numerical value, the hybrid pathway score is calculated by multiplication of the ratio with the negative log−10 of the 𝑃 value. Each signaling pathway considered was required to contain at least two unique proteins from either control or 3xTgAD datasets and possess a 𝑃 value of ≤.05. Unbiased network analysis was also performed on subsets of the primary protein sets that were specifically limited to transmembrane receptor proteins. The networks generated create predictions of the most likely functional interactions between proteins in a complex dataset [27]. Networks are created to indicate the most significant series of molecular interactions. The networks with the highest predictive “scores” possess the highest number of statistically significant “focus molecules”: “focus molecules” are proteins that are present in the most statistically-likely predicted functional network and are present in the input experimental dataset. The network “score” is a numerical value used to rank networks according to their degree of relevance to the input dataset. The “score” accounts for the number of experimental focus molecules (proteins) in the network and its size, as well as the total number of proteins in the Ingenuity Knowledge Base that could potentially be included in the specific networks. The network “score” is based on the hypergeometric distribution and is calculated with the right-tailed Fisher's Exact Test. Specific scientific textual associations between filtered protein sets (transmembrane receptor proteins IPA analysis) and Alzheimer’s disease processes were created using latent semantic indexing (LSI) algorithms using GeneIndexer (Computable Genomix, Incorporated: https://www.computablegenomix.com/geneindexer). GeneIndexer correlates the strength of association between specific factors (proteins) in a dataset with a user-defined interrogation term. GeneIndexer employs a 2010 murine or human database of over 1×10⁶ scientific abstracts to perform text-protein correlation analysis. LSI facilitates the specific textual interrogation of an input dataset with a specific term, that is, Alzheimer’s disease, to ascertain which of the input dataset proteins are explicitly associated with the interrogation term. Using LSI algorithms, not only is the direct interrogation term used to analyze the input dataset but also closely correlated additional terms, implicitly associated with the user-defined interrogation term, are also employed in the search patterns. A latent semantic indexing correlation score indicates the strength of association of the interrogation term and the specific proteins in the dataset. A highly relevant protein-term correlation yields a large number of explicitly/implicitly associated proteins with high LSI correlation scores. Therefore, a strong correlation between the proteins in a dataset and a specific user-defined interrogation term yields a large number of correlated proteins with high LSI correlation scores.

3. Statistical Analysis

Statistical analysis on multiple samples was performed using a standard nonparametric two-tailed Student’s 𝑡-test using 95% confidence limits. Analyses were computed using built-in software in GraphPad Prism v. 3.0a (GraphPad Software Inc., La Jolla, CA). Results are expressed as means ± SE. 𝑃 ≤.05 was considered statistically significant. For statistical analysis using Ingenuity Pathway Analysis v. 8.5 of signaling pathways and interaction network analysis, Fisher’s Exact test was employed with a 𝑃≤.05 cutoff. Network interaction scores were generated using a right-tailed Fisher's Exact Test.

4. Results

4.1. 3xTgAD Mice Demonstrate Impaired Learning and Memory Ability in the Morris Water Maze

Using the nonvisible Morris water maze trial and 16-month-old male control (C57-BL6) and 3xTgAD animals (𝑛=10 for both) we noted that the 3xTgAD mice demonstrated a significant reduction in their ability to find the location of the hidden platform (Figure 1). The 3xTgAD mice demonstrated significantly longer escape latencies and distances traveled compared to the control mice, while not showing any significant difference in calculated swim speed. Retention testing (three trials one week after the initial training) of these animals (control and 3xTgAD) also demonstrated a reduced cognitive capacity of the 3xTgAD mice compared to control (data not shown).

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Figure 1 

Morris Water Maze testing of control and 3xTgAD mice. (a) Distance travelled (cm) in the nonvisible probe target results for control (𝑛=10, blue bars) and 3xTgAD mice (𝑛=10, red bars) for 8 days of training. (b) Water maze escape latency (s) for days 1 to 8 of training in the nonvisible probe target. (c) Swim speed (cm/s) assessment of control and 3xTgAD animals during days 1–8 of training. *𝑃<.05; **𝑃<.01.

4.2. 3xTgAD Mice Demonstrate a Significant Alteration in Lipid Raft Density and Protein Marker Composition

Employment of the lipid raft isolation process described in the Methods section resulted in the clear visible isolation of a detergent-resistant lipid layer comprising centrifugal fractions 2–4 (Figure 1(a)). The lipid raft marker protein, flotillin-1, was demonstrated to be specifically enriched in these centrifugal fractions (2–4) (Figure 2(a)). The visual lipid density (absorbance units-background/square pixel) of the raft layers was quantified using Fuji-Film Image Gauge. Compared to control, both 8-month-old (Figure 2(c)) and 16-month-old (Figure 2(d)) 3xTgAD-derived centrifugal raft layers demonstrated a significant (8 months old 𝑃=.027, 𝑛=3; 16 months old 𝑃=.031, 𝑛=3) increase in buoyant detergent-insoluble density. This 3xTgAD increase in raft size, compared to control animals, demonstrated a strong association with a significant increase in expression of flotillin-1 in the raft fractions of 3xTgAD mice, especially in centrifugal fraction 2 (Figure 2(e), 𝑃=.017, 𝑛=3). Equal levels of total protein (measured using BCA and also SYPRO gel staining) were employed for each Western blot of the raft extracts. Quantification of fraction 2 was chosen, as this reliably indicated the greatest enrichment of this lipid raft marker. Similar quantitative alterations in expression of flotillin-1 between control and 3xTgAD mice were also seen in the additional lipid raft centrifugal fractions, that is, 3 and 4. Qualitatively similar results, with respect to 3xTgAD mouse lipid raft density and flotillin-1 expression were noted in parallel experiments carried out with age-matched female mice. In addition we also noted a similar qualitative lipid raft expression of flotillin-1 trend in male human cortex tissue (data not shown). These latter data and their significance to our current data will be further addressed in subsequent manuscripts.

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Figure 2 

Quantification of detergent-resistant lipid rafts. (a) The pictorial panel depicts an image of iodixanol-separated detergent resistant membrane fractions (centered on red arrow), captured using a Nikon 3200 digital camera. The line diagram indicates the direction of collection of centrifugal fractions 1–10, and the associated Western blot for flotillin-1 demonstrates its enrichment in the raft fractions. (b) Captured Joint Photographic Expert Group (JPG) images were converted to a Tagged Image File Format (TIFF) version and imported to Image Gauge (v4.2) software and the specific area of interest (red box), that is, the detergent-resistant, flotillin-1-rich lipid raft band was quantified into absorbance units minus background absorbance per square pixel area ((AU-B)/px2) values. (c) Representative set of male 8-month-old control (1) and 3xTgAD (2) mice detergent-resistant membranes isolated from plasma membrane fractions separated using an Iodixanol gradient. The associated histogram depicts mean ± s.e. (standard error) mean detergent-resistant membrane intensity ((AU-B)/px2) from at least three separate control and 3xTgAD mice (𝑃=.033, nonpaired, two-tailed 𝑡-test). (d) Representative set of male 16-month-old control (1) and 3xTgAD (2) mice detergent resistant membranes isolated from plasma membrane fractions separated using an Iodixanol gradient. The associated histogram depicts mean ± s.e. (standard error) mean detergent resistant membrane intensity ((AU-B)/px2) from at least three separate C57-BL6 and 3xTgAD mice (𝑃=.0224, non-paired, two-tailed 𝑡-test). (e) Representative flotillin-1 Western blot for the lipid raft fraction series for 3xTgAD (red outline) or control (C57-BL6: blue outline) mice. The associated histogram depicts mean ± s.e. (standard error) mean fraction 2 flotillin expression intensity ((AU-B)/px2) from at least three separate C57-BL6 and 3xTgAD mice (𝑃=.015, non-paired, two-tailed 𝑡-test).

4.3. Differential Protein Expression in Lipid Rafts Isolated from 3xTgAD Mice Compared to Control Mice

Using an un-biased proteomic analysis of replicate lipid raft extracts, we were able to identify (from at least two individual nonambiguous peptides) multiple proteins in both control and 3xTgAD cortical extracts (control, Appendix A; 3xTgAD, Appendix B). When comparing the relative differences in lipid raft protein expression, only a small minority (17%: Figure 3(a)) of identified proteins were substantively identified in both control and 3xTgAD raft samples; however many of these common proteins identified were differentially detected (see Supplementary Table 1 in Supplementary Material available online at http://dx.doi.org/10.4061/2010/604792). To verify the relative differential expression of multiple proteins in the control versus 3xTgAD lipid raft extracts, we also performed multiple Western blot analyses of raft centrifugal fraction-2 (F-2) samples. With loading of total equal protein quantities (50 μg: assessed in an unbiased manner with SYPRO-Ruby: Figure 3(b)) of either control or 3xTgAD F-2 samples, we assessed the relative differential expression of multiple proteins (Figures 3(c)–3(n)). From the Western blot analysis it was consistently demonstrated that differential qualitative protein detection in control versus 3xTgAD raft samples strongly correlated with differential semiquantitative protein expression. Hence, the absence of consistent MS-based detection of Pyk2 (Figure 3(d)), Jak2 (Figure 3(f)), Fyn (Figure 3(h)), paxilin (Figure 3(i)), IRS-1 (Figure 3(j)), caspase 7 (Figure 3(k)), mTOR/FRAP1 (Figure 3(l)) and IGF-1R (Figure 3(n)) in control raft sample correlated to their significantly lower expression in control raft F-2 samples, compared to that in 3xTgAD samples. Conversely, the absence of consistent MS-based detection of FAK (Figure 3(c)), GIT-1 (Figure 3(e)), Crk (Figure 3(g)), and Grin2 (Figure 3(m)), correlated to their significantly lower expression in 3xTgAD raft F-2 samples, compared to that in control samples.

Figure 3 

Differential protein expression in control versus 3xTgAD lipid raft extracts. (a) Proportionately drawn Venn diagram analysis of reliably identified proteins from control lipid rafts (blue line) and 3xTgAD rafts (red line). (b) Total protein loading control for centrifugal fraction 2. A total of 50 mg of fraction 2 protein was loaded and stained with SYPRO Ruby and scanned using a phosphorimager. (c)–(n). Representative western blots from multiple expression analysis experiments for differential presentation of proteins in fraction 2 extracts from control (blue) or 3xTgAD mice (red). Associated with each panel (c)–(n) the associated histograms represent the mean ± s.e. mean of protein expression intensity (measured in ((AU-B)/px2)) from at least three separate experiments. *𝑃<.05; **𝑃<.01; ***𝑃<.001. Protein abbreviations are as follows. FAK: focal adhesion kinase; Pyk2: proline-rich tyrosine kinase 2; GIT-1: GRK interactor-1; Jak2: Janus kinase 2; Crk: v-Crk avian sarcoma virus CT10 oncogene homolog; Fyn: Fyn tyrosine kinase; IRS-1: insulin receptor substrate-1; casp 7: caspase 7; mTOR: mammalian target of rapamycin; Grin2: G protein-regulated inducer of neurite outgrowth 2; IGF-1R: insulin-like growth factor-1 receptor.

4.4. Functional Signaling Cluster Analysis of Control versus 3xTgAD Lipid Raft Proteomes

As our MS-based multidimensional protein identification process identified several hundred proteins from each control or 3xTgAD lipid raft sample, we employed a bioinformatic analysis process to assess the relative functionalities of both the control versus 3xTgAD raft protein lists. As the majority of cellular signaling processes are mediated and regulated by multiple groups of proteins interacting with each other, we clustered, in a statistically significant manner, proteins in control or 3xTgAD animal raft samples into functional signaling groups. To assess the relative changes in regulation of classical signaling pathways, we applied a subtractive approach for the pathway “hybrid” scores (indicative of the “activity” of the specific signaling pathway: calculated by significant expression enrichment ratio of proteins in that pathway multiplied by the negative log₁₀ (−log₁₀) of the probability of the pathway enrichment). For each specific common signaling pathway, our mathematical approach subtracted control pathway “hybrid” scores from the pathway “hybrid” scores generated from the 3xTgAD protein set. Hence, a positive result of this subtraction indicates a greater activity of this functional pathway in 3xTgAD animals, and a negative score indicates a greater activity of this functional pathway in the control animals. Analysis of pathways involved in cellular signaling (Figure 4(a): proteins and scores in associated Appendix C) demonstrated that pathways commonly associated with cell stress responses were highly activated in 3xTgAD rafts, for example “p53 signaling”, “p38 mitogen-activated protein kinase (MAPK) signaling”, and “stress-activated protein kinase (SAPK)/JNK pathways”. In a stark contrast, prosurvival synaptic connectivity and neurotransmissive pathways were more profoundly activated in the control mice, for example, “tight junction signaling”, “calcium signaling”, “PTEN signaling”, and “Wnt/β-catenin signaling”. To investigate the specific neuronal functional effects of these disparate signaling activities, we next studied the significant clustering of raft proteins into neuron-functional pathways (Figure 4(b): Appendix D). As one would expect, the 3xTgAD mice raft protein clustering revealed a considerably greater (relative to control) activation of multiple neurodegenerative neuronal processes including: “amyloid processing”, “Amyotrophic lateral sclerosis”, “Huntington’s disease signaling” and “Parkinson’s signaling”. In addition to the greater activation of these degenerative processes, the 3xTgAD mice also demonstrated profound changes in the significant clustering of proteins into cytoskeletal remodeling groups (“actin cytoskeleton signaling”, regulation of actin-based motility by Rho’) compared to the control mice. In accordance with our demonstration of the significant diminution of the learning and memory ability of the 3xTgAD mice, it was striking to notice the profoundly greater activation of neuron-functional pathways that control synaptic learning-dependent processes (i.e., “synaptic long-term depression”, “axonal guidance signaling”,and “synaptic long-term potentiation”) in the control mice compared to the 3xTgAD mice. Considerable evidence from multiple experimental studies has recently underlined the importance of the regulation of energy metabolism in controlling the aging process and neurodegenerative disorders [28–30]. Upon inspection of the relative differences in the activation of energy-regulatory pathways created by clustering of control raft proteins versus 3xTgAD raft proteins, a profound functional distinction was noted (Figure 4(c): Appendix E). In control animals versus 3xTgAD, there was a considerably stronger activation of energy-generating pathways connected to the use of the primary metabolic substrate, that is, sugars (“amino sugars metabolism”, “glycolysis/gluconeogenesis”, and “pentose phosphate pathway”). In contrast, the energy regulatory pathways that were more strongly associated with the 3xTgAD animals involved energy derivation from alternative energy sources, for example, “synthesis and degradation of ketone bodies”, “butanoate metabolism”, and “fatty acid biosynthesis”. Many of the alterations in energy regulation in aging and degenerative disorders are thought to be associated with adaptive responses to the induction of cellular stresses, potentially through toxic effects of Aβ, NFTs and accumulated oxidative damage [30]. When the raft proteins from control and 3xTgAD mice were clustered into functional stress response pathways, again a stark contrast in the control- or 3xTgAD-associated pathways was demonstrated (Figure 4(d): Appendix F). In the 3xTgAD mice raft clustering it was noted that the association of energy-associated stressful and neuronal damage-related pathways (“PPARα/RXRα activation”, “hypoxia signaling”, “apoptosis signaling”, and “endoplasmic reticulum stress pathway”) was considerably stronger than in the control mice. Indicating a correlated connection between stress response capacity and AD pathology, there was a considerably greater association of the “Nrf2-mediated oxidative stress response pathway” in control mice compared to the 3xTgAD. Therefore, the 3xTgAD mice may demonstrate excessive neuronal stress and damage due to the attenuated activation of such stress response pathways in lipid rafts of AD synapses.

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Figure 4 

Functional pathway informatic clustering of control and 3xTgAD lipid raft proteins. (a) Subtractive representation of hybrid score generation after clustering of lipid raft proteins from control and 3xTgAD animal rafts into cellular signaling pathways. The hybrid scores were generated by multiplication of the protein enrichment ratio of the specific pathway with the negative log10 (−log10) of the probability of that enrichment (see Section 2). The data is presented as a numerical value of the control pathway hybrid score subtracted from the 3xTgAD pathway hybrid score. Pathways in which the score in 3xTgAD was greater than the control are denoted in red; pathways in which the control hybrid score is greater than the 3xTgAD hybrid score are denoted in blue. A similar depiction format is employed for differential analysis of control versus 3xTgAD Neuronal Function pathways (b), Energy Regulation/Metabolism pathways (c), and Stress Response pathways (d).

4.5. Functional Receptor Signaling Cluster Analysis of Control versus 3xTgAD Lipid Raft Proteomes

As one of the most important functions of synaptic lipid rafts is to congregate transmembrane or juxtamembrane receptor systems [31], we next performed an in-depth investigation of the significant differential functional clustering of receptor signaling pathways between control and 3xTgAD rafts. Upon functional clustering of the raft proteins into receptor signaling pathways, strong differences in pathways association between control and 3xTgAD mice were noted (Figure 5: Appendix G). Some of the strongest differences were noted by the considerably poorer activation of growth factor-related signaling (“PDGF signaling”, “EGF signaling”, and “FGF signaling”), structural trans-synaptic receptor signaling (“Neuregulin signaling” and “Ephrin receptor signaling”), excitatory signaling (glutamate receptor signaling) and neurodevelopmental signaling (Sonic hedgehog signaling) pathways in the 3xTgAD mice, compared to the control mice. The receptor signaling profile of the 3xTgAD mice demonstrated a more profound association compared to control mice for pathways linked to inhibitory synaptic signaling (“GABA receptor signaling” and “Aryl hydrocarbon receptor signaling”: [32]), amyloid processing (“Notch signaling” and “Integrin signaling”: [33]), and neuronal stress (glucocorticoid receptor signaling). Transmembrane receptor signaling by systems including receptor tyrosine kinases or G protein-coupled receptors (GPCRs) represents one of the most important signaling mechanisms of neuronal synaptic regulation [34]. However, the activation of transmembrane receptor systems and the stimulation of their intracellular signaling cascades, especially for GPCRs, is now considered to be far more complex and intricate than initially proposed by two-state receptor models [34, 35]. Much of this additional signaling diversity is thought to arise from the additional complexity of receptor-accessory scaffolding protein modification of receptor signaling [35]. To appreciate the multiple connections between receptor (and GPCR in particular) activity and the presence of neurophysiological deficits in AD, we performed a multidimensional analysis of the proteins present in control or 3xTgAD mice. Using the novel, un-biased, bioinformatic GeneIndexer latent semantic indexing (LSI) process (https://www.computablegenomix.com/geneindexer.php), explicit correlations can be made between protein/gene factors from input datasets and their linkage (in over 1×10⁶ curated scientific abstracts) to a specific interrogation term, for example, Alzheimer’s. The semantic indexing algorithms of GeneIndexer also allow for multidimensional correlations to be measured for terms significantly related to the interrogation term, hence providing a flexible, intelligent query process. For the control and 3xTgAD datasets, we employed multiple interrogation terms targeted to demonstrate differences between control and 3xTgAD datasets. Using the following interrogation terms: Alzheimer’s, oxidation, neurodegeneration, synaptic transmission, neurogenesis, scaffolding, and GPCR, we demonstrated that, at a multidimensional interactive level, there is minimal functional cross-over between control and 3xTgAD raft samples (Figure 6: Appendix H). Only proteins that demonstrated explicit correlations (latent semantic indexing score of ≥0.1) to at least two of the interrogation terms are denoted in the multidimensional heatmap (Figure 6: Appendix H). Therefore, each of the proteins identified in the heatmap are strongly correlated with many of the connected interrogation terms and therefore show potential synergistic activity. Analysis of identified proteins in this manner, that is, selected specifically for multidimensional neurological roles, allows for an un-biased focusing on proteins that may possess keystone-like functions in the molecular signaling networks involved in neurodegeneration. With respect to specific interrogation terms, a strong validation of the technique is demonstrated by the fact that using the Alzheimer’s interrogation term, 47 3xTgAD-unique multidimensional proteins were indicated while only 10 such multidimensional proteins were shown in control rafts (Figure 6). Confirming a strong role of oxidative damage, 21 3xTgAD-unique multidimensional proteins were present in the oxidation results while only 6 such control-unique were demonstrated. Interestingly and perhaps suggestive of a potential future line of AD research was the observation that considerably fewer multidimensional 3xTgAD-unique proteins were associated with the process of neurogenesis (15), compared to the 32 control-unique multidimensional proteins associated with this neuroprotective mechanism. In accordance with the important role of receptor systems in AD, we additionally noted that more 3xTgAD-unique proteins were associated with GPCRs (27) compared to control-unique GPCR-related multidimensional proteins (16).

Figure 5 

Functional receptor signaling pathway informatic clustering of control and 3xTgAD lipid raft proteins. Subtractive representation of hybrid score generation after clustering of raft proteins from control and 3xTgAD animal rafts into receptor signaling pathways. The data is presented as a numerical value of the control pathway hybrid score subtracted from the 3xTgAD pathway hybrid score. Pathways in which the score in 3xTgAD was greater than the control are denoted in red; pathways in which the control hybrid score was greater than the 3xTgAD hybrid score are denoted in blue.

Figure 6 

Multidimensional protein latent semantic indexing (LSI) analysis of proteins extracted from control and 3xTgAD lipid rafts. Proteins from the control or 3xTgAD extracted datasets that possessed an explicit latent semantic indexing (LSI, GeneIndexer, Computable Genomix) score in at least two of the multiple GeneIndexer interrogation terms (Alzheimer’s, oxidation, neurodegeneration, synaptic transmission, neurogenesis, scaffolding, and GPCR) are represented in a heatmap format. Proteins are identified on the left side of the heatmap as an individual number (see Appendix H for key). The presence of a colored panel (3xTgAD, red: control, blue: 3xTgAD and control: yellow) on the same lateral as the numbered protein denotes explicit textual correlation of that protein with the specific vertical interrogation term.

4.6. Functional Interaction Networks of Receptor Signaling Proteins in Control versus 3xTgAD Lipid Raft Proteomes

From our investigation of the multidimensional nature of raft proteins with respect to neurodegenerative processes, it is clear that there are many factors that are highly likely to work together in complex and intricate functional networks. To investigate the nature of the most statistically likely functional network interactions, we employed IPA network analysis of a receptor-filtered (using IPA-knowledge base data filtering, IPA v. 8,5) subset of the control or 3xTgAD raft protein datasets (Tables 1 and 2, resp.). Using these datasets, un-biased network analysis is able to predict the most likely series of functional interactions (based on empirically derived experimental evidence) that take place between the receptor-associated raft proteins. The control and 3xTgAD receptor-specific filtered datasets demonstrated a relatively minimal overlap, that is, 11.6% commonality, indicating that substantial alterations of these proteins may occur in the rafts of 3xTgAD animals (Figure 7(a)). The most statistically likely interaction network that was predicted to occur in control mice centered on neuroprotective and neurotransmissive factors such as phosphoinositide-3-kinse (PI3K), Akt-1, muscarinic GPCRs (Chrm5), and glutamate receptors (Grm5) (Figure 7(a): Appendix I). In contrast, the highest statistically scoring network from 3xTgAD receptor-specific proteins was centered on lipid-regulating factors and stress-related factors including: p38 MAPK; Jnk (c-jun N-terminal kinase), Lrpap1 (low-density lipoprotein receptor-related protein associated protein 1); LDL (low density lipoprotein), and NF-κB (Figure 7(b): Appendix J). Therefore, at the level of functional interaction of receptor-related proteins in the lipid rafts, it is clear that these membrane microdomains are a strong functional locus of this degenerative disease. Reinforcing this AD-relevant microcosm effect in the lipid rafts we analyzed, using latent semantic indexing (LSI) interrogation of these receptor-specific datasets (Table 2—control; Appendix I-3xTgAD), the Alzheimer’s disease correlation of these receptor-specific proteins. In Figure 8, we demonstrate that almost twice as many proteins in the 3xTgAD dataset (21) explicitly correlated with the interrogation term Alzheimer’s disease compared to the proteins in the control dataset (11). The degree of correlation of the interrogation term (Alzheimer’s) to each specific protein is indicated by the LSI score. In Figure 8(b) the cumulated LSI score for the 3xTgAD Alzheimer’s-related proteins was 2.92 while for the control proteins only 1.21 (Figure 8(b)), demonstrating that a much stronger correlation of receptor-associated proteins existed for the proteins in 3xTgAD rafts, compared to control. Upon comparison of the phylogenetic relationships of the receptor-specific proteins that form the most likely functional networks (from Figure 7(b)), it is clear that for the control-set proteins only three of these in this network are highly correlated to reports of Alzheimer’s disease (27.2%: Figure 8(c)) while the most coherent interaction network of 3xTgAD raft proteins possessed a much higher percentage of Alzheimer’s disease-related proteins (62%: Figure 8(d)). Therefore, this suggests that one of the important pathological loci of AD could be the disruption of interactivity of receptor-associated proteins in the lipid raft microdomains and that such a finding can be uncovered in a completely un-biased informatic format from extremely large and difficult to interpret datasets.

Table 1 

Receptor-specific protein list from lipid raft extracts from control animals. Primary protein lists of extracted lipid raft proteins were filtered for a specific receptor profile using IPA v. 8.5.

Table 2 

Receptor-specific protein list from lipid raft extracts from 3xTgAD animals. Primary protein lists of extracted lipid raft proteins were filtered for a specific receptor profile using IPA v. 8.5.

(a)

(b)

(c)

Figure 7 

Receptor-restricted control and 3xTgAD network interaction analysis. (a) Proportionally drawn Venn diagram depicting the relative distribution between control or 3xTgAD raft samples of receptor-specific proteins filtered using IPA version 8.5 (control filtered protein list, Table 1; 3xTgAD filtered protein list, Table 2). (b) The highest scoring protein interaction network generated from IPA Network analysis (network scores and focus molecules are listed in Appendix I) of the receptor-specific control dataset. (c) The highest scoring protein interaction network generated from IPA Network analysis (network scores and focus molecules are listed in Appendix I) of the receptor-specific 3xTgAD dataset (Appendix J). A full description of the nature of interactions based on the connecting lines can be found at the following webpage linked to the IPA analysis module (https://analysis.ingenuity.com/pa/info/help/help.htm#ipa_help.htm). Dashed lines represent indirect gene interactions while solid lines represent empirically measured direct interactions. The two highest significantly scoring networks (B—control, C—3xTgAD) are based on the highest percentage of the network occupation by specific proteins (focus molecules) from the input receptor-specific datasets.

(a)

(b)

(c)

(d)

Figure 8 

Alzheimer’s disease correlation of control or 3xTgAD receptor-specific lipid raft proteins. (a) The histogram represents the number of receptor-specific raft proteins (Table 1: control, Table 2: 3xTgAD) that demonstrate an explicit LSI correlation to the term “Alzheimer’s” for control (blue) or 3xTgAD (red) extracts. (b) The histogram depicts the cumulated LSI correlation scores for the Alzheimer’s-related receptor-specific proteins identified in (a). panels (c) and (d) represent the phylogenetic dendrograms for the receptor-specific raft proteins linked to the interrogation term “Alzheimer’s” from control (c) or 3xTgAD (d) datasets. The proteins highlighted in red or blue and indicated by an arrow were specifically clustered into the highest scoring protein interaction networks for control (Figure 7(b)) or 3xTgAD (Figure 7(c)) samples.

5. Discussion

Multiple informatic techniques were employed to investigate and elucidate the nature of functional protein interactions that occur differentially in the lipid raft microdomains of control versus 3xTgAD Alzheimer’s disease mice. Cognitively impaired male 3xTgAD mice showed profound differences in the protein constituents of lipid raft extracts compared to age-matched control mice, that is, only 17% of raft proteins were similar between the two groups of mice. Our microdomain proteomic approach was able to specifically assist in the identification of altered proteins that are highly characteristic of AD-related raft pathophysiology, for example, the Src-family tyrosine kinase Fyn (Figure 3(h)) [19, 20].

Currently, biological scientists are often faced with complex biological issues concerning the interpretation of their results due to the development of facile mass data acquisition technologies, that is, extracting relevant and illuminating information from large datasets is often extremely challenging. However, with the application of multiple, sequential un-biased informatic processes, we were able to identify specific lipid raft involvement in altered pathways that can control multiple degenerative mechanisms, for example, attenuation of the Wnt/β-catenin signaling pathway, profound reduction of the important Nrf2 stress response pathway (Figure 4(d)), the loss of neurogenesis association, and the important involvement of synaptic GPCR-systems (Figure 6) in the 3xTgAD mice [36–38].

Elucidation of the crucial signaling relationships in this degenerative disorder, and the identity of the proteins that mediate them, could lead to the more rational development of novel therapeutics for Alzheimer’s disease. Using our informatic receptor-targeted approach, we were also able to reinforce the validity of our discovery process by also identifying the importance of energy-related insulin/insulin-like growth factor (IGF) signaling in AD (Figures 3(j), 3(n), 5, and 8(d)) that has recently become more widely appreciated by other researchers [39–42]. In addition to IGF receptor activity, we noted a potential implication of the presynaptic latrophilins (lphn) in AD pathophysiology (Figure 8(d)). These unique receptors form the high affinity target of α-latrotoxin and may be able to integrate presynaptic calcium regulation with an ability to potentially physically interact with the postsynaptic neuron [43]. Another receptor signaling system that our analysis revealed to possess a potential role in AD is the Sonic Hedgehog (Shh) systems (Figures 5 and 8(d)). With a specific correlation to AD pathophysiology, it has been demonstrated that Shh can act in a synergistic manner with nerve growth factor to act on central nervous system cholinergic neurons [44], and cholinergic insufficiency has been strongly associated with cognitive decline and Alzheimer’s-related pathophysiology [45].

6. Conclusions

The combined use of broad range proteomic analysis, with sequential multidimensional informatic analysis enables the determination of important correlations between pathophysiology and functional protein differences. Using discrete proteomes, that is, lipid raft extracts, versus whole-cell/tissue proteomes, facilitates an improved ability to understand the complex interactivity between transmembrane receptor protein systems in a disease setting. The appreciation and clustering of protein datasets into coherent groups greatly increases our capacity to focus upon potentially important therapeutic target networks. The knowledge gained of protein activity networks may greatly assist in the future development of network-targeting therapeutics that possess a multidimensional efficacy at several interacting proteins.

Appendices

A.

Lipid raft-derived extracted proteins from control mouse 16-month-old cortical tissue. Specific proteins isolated from control mouse cortex were identified with multidimensional protein identification technology (MudPIT) LC MS/MS. Each protein was identified in at least two out of three experimental replicate animals and from at least two isolated peptides per protein. The following are the protein symbol and its corresponding definitions.Atm: ataxia telangiectasia mutatedBcat1: branched chain aminotransferase 1, cytosolicBcl11a: B-cell CLL/lymphoma 11A (zinc finger protein)Bnip1: BCL2/adenovirus E1B 19 kDa interacting protein 1Brd2: bromodomain containing 2Bteb1: Kruppel-like factor 9Bzrap1: benzodiazepine receptor (peripheral) associated protein 1C3: complement component 3C5: complement component 5Cacna1a: calcium channel, voltage-dependent, P/Q type, alpha 1A subunitCacna1c: calcium channel, voltage-dependent, L type, alpha 1C subunitCacna2d2: calcium channel, voltage-dependent, alpha 2/delta subunit 2Cadps: Ca++-dependent secretion activatorCalb1: calbindin 1, 28 kDaCalb2: calbindin 2Calm2: calmodulin 2 (phosphorylase kinase, delta)Camkk1: calcium/calmodulin-dependent protein kinase kinase 1, alphaCamkk2: calcium/calmodulin-dependent protein kinase kinase 2, betaCap1: CAP, adenylate cyclase-associated protein 1 (yeast)Cast: calpastatinCat: catalaseCatsper2: cation channel, sperm associated 2Cav1: caveolin 1, caveolae protein, 22 kDaCblb: Cas-Br-M (murine) ecotropic retroviral transforming sequence bCbp: opsin 1 (cone pigments), long-wave-sensitiveCbr1: carbonyl reductase 1Cbwd1: COBW domain containing 1Cbx5: chromobox homolog 5 (HP1 alpha homolog, Drosophila)Ccbl1: cysteine conjugate-beta lyase, cytoplasmicCcin: calicinCcl28: chemokine (C-C motif) ligand 28Ccl4: chemokine (C-C motif) ligand 4ccnb1: cyclin B1Ccnc: cyclin CCct2: chaperonin containing TCP1, subunit 2 (beta)Cct3: chaperonin containing TCP1, subunit 3 (gamma)Cct4: chaperonin containing TCP1, subunit 4 (delta)Cct5: chaperonin containing TCP1, subunit 5 (epsilon)Cct6a: chaperonin containing TCP1, subunit 6A (zeta 1)Cd1: ribosomal protein L5Cd151: CD151 molecule (Raph blood group)Cd200: CD200 moleculeCd276: CD276 moleculeCd2ap: CD2-associated proteinCd4: CD4 moleculeCdc10: septin 7Cdc25b: cell division cycle 25 homolog B (S. pombe)Cdc42: cell division cycle 42 (GTP binding protein, 25 kDa)Cdc42bpa: CDC42 binding protein kinase alpha (DMPK-like)Cdc5l: CDC5 cell division cycle 5-like (S. pombe)Cdh1: cadherin 1, type 1, E-cadherin (epithelial)Cdh10: cadherin 10, type 2 (T2-cadherin)Cdh2: cadherin 2, type 1, N-cadherin (neuronal)Cdh4: cadherin 4, type 1, R-cadherin (retinal)Cdk2: cyclin-dependent kinase 2Cdk5rap2: CDK5 regulatory subunit associated protein 2Cdk5rap3: CDK5 regulatory subunit associated protein 3Cdk6: cyclin-dependent kinase 6Cdk7: cyclin-dependent kinase 7Cdkl2: cyclin-dependent kinase-like 2 (CDC2-related kinase)Cdkl3: cyclin-dependent kinase-like 3Cdkn1b: cyclin-dependent kinase inhibitor 1B (p27, Kip1)Cds1: CDP-diacylglycerol synthase (phosphatidate cytidylyltransferase) 1Cdv1: intraflagellar transport 81 homolog (Chlamydomonas)Cebpe: CCAAT/enhancer binding protein (C/EBP), epsilonCebpz: CCAAT/enhancer binding protein (C/EBP), zetaCelsr2: cadherin, EGF LAG seven-pass G-type receptor 2 (flamingo homolog, Drosophila)Celsr3: cadherin, EGF LAG seven-pass G-type receptor 3 (flamingo homolog, Drosophila)Cend1: cell cycle exit and neuronal differentiation 1Cenpf: centromere protein F, 350/400ka (mitosin)Centa1: ArfGAP with dual PH domains 1Centg1: ArfGAP with GTPase domain, ankyrin repeat and PH domain 2Cep350: centrosomal protein 350 kDaCes1: carboxylesterase 1 (monocyte/macrophage serine esterase 1)Ces3: carboxylesterase 3Cetn2: centrin, EF-hand protein, 2Cetn3: centrin, EF-hand protein, 3 (CDC31 homolog, yeast)Cfh: complement factor HCfl1: cofilin 1 (nonmuscle)Chd3: chromodomain helicase DNA binding protein 3Chd4: chromodomain helicase DNA binding protein 4Chga: chromogranin A (parathyroid secretory protein 1)Chl1: cell adhesion molecule with homology to L1CAM (close homolog of L1)Chmp1a: chromatin modifying protein 1AChn2: chimerin (chimaerin) 2Chrm5: cholinergic receptor, muscarinic 5Chrnb3: cholinergic receptor, nicotinic, beta 3Chrnb4: cholinergic receptor, nicotinic, beta 4Chrng: cholinergic receptor, nicotinic, gammaChst7: carbohydrate (N-acetylglucosamine 6-O) sulfotransferase 7Chx10: visual system homeobox 2Cirbp: cold inducible RNA binding proteinCit: citron (rho-interacting, serine/threonine kinase 21)Cktsf1b1: gremlin 1, cysteine knot superfamily, homolog (Xenopus laevis)Clasp2: cytoplasmic linker associated protein 2Clcc1: chloride channel CLIC-like 1Clcn7: chloride channel 7Cldn1: claudin 1Cldn19: claudin 19Cldn4: claudin 4CLEC10A: C-type lectin domain family 10, member AClecsf6: C-type lectin domain family 4, member AClic4: chloride intracellular channel 4CLIP3: CAP-GLY domain containing linker protein 3Clpb: ClpB caseinolytic peptidase B homolog (E. coli)Clstn1: calsyntenin 1Cltb: clathrin, light chain (Lcb)Cndp2: CNDP dipeptidase 2 (metallopeptidase M20 family)Cnga1: cyclic nucleotide gated channel alpha 1Cnga4: cyclic nucleotide gated channel alpha 4Cnksr2: connector enhancer of kinase suppressor of Ras 2Cnot6: CCR4-NOT transcription complex, subunit 6Cnp: 2^',3^'-cyclic nucleotide 3^' phosphodiesteraseCnr1: cannabinoid receptor 1 (brain)Cntfr: ciliary neurotrophic factor receptorCntn1: contactin 1Cog3: component of oligomeric golgi complex 3Colm: gliomedinCopa: coatomer protein complex, subunit alphaCopb1: coatomer protein complex, subunit beta 1COPB2: coatomer protein complex, subunit beta 2 (beta prime)Cops4: COP9 constitutive photomorphogenic homolog subunit 4 (Arabidopsis)Cops8: COP9 constitutive photomorphogenic homolog subunit 8 (Arabidopsis)Coro1a: coronin, actin binding protein, 1ACoro7: coronin 7Cp: ceruloplasmin (ferroxidase)Cpe: carboxypeptidase ECplx1: complexin 1Cpt1a: carnitine palmitoyltransferase 1A (liver)Cpt2: carnitine palmitoyltransferase 2Crabp2: cellular retinoic acid binding protein 2Crhbp: corticotropin releasing hormone binding proteinCrip2: cysteine-rich protein 2Crk: v-crk sarcoma virus CT10 oncogene homolog (avian)Crkl: v-crk sarcoma virus CT10 oncogene homolog (avian)-likeCrmp1: collapsin response mediator protein 1Crnkl1: crooked neck pre-mRNA splicing factor-like 1 (Drosophila)Crp: C-reactive protein, pentraxin-relatedCry1: cryptochrome 1 (photolyase-like)Crygc: crystallin, gamma CCrygs: crystallin, gamma SCrym: crystallin, muCs: citrate synthaseCsf1: colony stimulating factor 1 (macrophage)Csnk1e: casein kinase 1, epsilonCsnk1g2: casein kinase 1, gamma 2Csnk2a1: casein kinase 2, alpha 1 polypeptideCsnk2b: casein kinase 2, beta polypeptideCspg2: versicanCspg3: neurocanCspg5: chondroitin sulfate proteoglycan 5 (neuroglycan C)Cspg6: structural maintenance of chromosomes 3Cst6: cystatin E/MCstb: cystatin B (stefin B)Ctf1: cardiotrophin 1Cthrc1: collagen triple helix repeat containing 1Ctla4: cytotoxic T-lymphocyte-associated protein 4Ctnnb1: catenin (cadherin-associated protein), beta 1, 88 kDaCtnnd2: catenin (cadherin-associated protein), delta 2 (neural plakophilin-related arm-repeat protein)Ctrb: chymotrypsinogen B1Ctrl: chymotrypsin-likeCtsd: cathepsin DCttn: cortactinCttnbp2: cortactin binding protein 2Cul1: cullin 1Cul5: cullin 5Cuta: cutA divalent cation tolerance homolog (E. coli)Cutl1: cut-like homeobox 1CX3CL1: chemokine (C-X3-C motif) ligand 1Cxadr: coxsackie virus and adenovirus receptorCxcl2: chemokine (C-X-C motif) ligand 2Cyb5: cytochrome b5 type A (microsomal)Cyb5b: cytochrome b5 type B (outer mitochondrial membrane)Cyb5r1: cytochrome b5 reductase 1Cybb: cytochrome b-245, beta polypeptideCyln2: CAP-GLY domain containing linker protein 2Cyp2s1: cytochrome P450, family 2, subfamily S, polypeptide 1Cyr61: cysteine-rich, angiogenic inducer, 61Dab2: disabled homolog 2, mitogen-responsive phosphoprotein (Drosophila)Dab2ip: DAB2 interacting proteinDad1: defender against cell death 1Dag1: dystroglycan 1 (dystrophin-associated glycoprotein 1)Dap: death-associated proteinDapk3: death-associated protein kinase 3Dbc1: deleted in bladder cancer 1DBH: dopamine beta-hydroxylase (dopamine beta-monooxygenase)Dbn1: drebrin 1Dbndd2: dysbindin (dystrobrevin binding protein 1) domain containing 2Dbnl: drebrin-likeDcd: dermcidinDci: dodecenoyl-Coenzyme A delta isomerase (3,2 trans-enoyl-Coenzyme A isomerase)Dclk2: doublecortin-like kinase 2Dclre1c: DNA cross-link repair 1C (PSO2 homolog, S. cerevisiae)Dctn2: dynactin 2 (p50)Ddah2: dimethylarginine dimethylaminohydrolase 2Ddb1: damage-specific DNA binding protein 1, 127 kDaDdn: dendrinDdost: dolichyl-diphosphooligosaccharide-protein glycosyltransferaseDdr2: discoidin domain receptor tyrosine kinase 2Ddt: D-dopachrome tautomeraseDdx1: DEAD (Asp-Glu-Ala-Asp) box polypeptide 1Ddx17: DEAD (Asp-Glu-Ala-Asp) box polypeptide 17Ddx47: DEAD (Asp-Glu-Ala-Asp) box polypeptide 47Ddx5: DEAD (Asp-Glu-Ala-Asp) box polypeptide 5Decr1: 2,4-dienoyl CoA reductase 1, mitochondrialDes: desminDgcr14: DiGeorge syndrome critical region gene 14Dgkb: diacylglycerol kinase, beta 90 kDaDgkg: diacylglycerol kinase, gamma 90 kDaDhcr7: 7-dehydrocholesterol reductaseDhodh: dihydroorotate dehydrogenaseDhrs8: hydroxysteroid (17-beta) dehydrogenase 11Dhx16: DEAH (Asp-Glu-Ala-His) box polypeptide 16Dhx30: DEAH (Asp-Glu-Ala-His) box polypeptide 30Dia1: cytochrome b5 reductase 3Dio1: deiodinase, iodothyronine, type IDisc1: disrupted in schizophrenia 1Dkc1: dyskeratosis congenita 1, dyskerinDlat: dihydrolipoamide S-acetyltransferaseDlc1: deleted in liver cancer 1Dld: dihydrolipoamide dehydrogenaseDlgap1: discs, large (Drosophila) homolog-associated protein 1Dlgap2: discs, large (Drosophila) homolog-associated protein 2Dlgap4: discs, large (Drosophila) homolog-associated protein 4Dll1: delta-like 1 (Drosophila)Dll3: delta-like 3 (Drosophila)Dlx5: distal-less homeobox 5Dmd: dystrophinDmn: synemin, intermediate filament proteinDmrt1: doublesex and mab-3 related transcription factor 1Dnah6: dynein, axonemal, heavy chain 6Dnaja2: DnaJ (Hsp40) homolog, subfamily A, member 2Dnch1: dynein, cytoplasmic 1, heavy chain 1Dncl2a: dynein, light chain, roadblock-type 1Dntt: deoxynucleotidyltransferase, terminalDock9: dedicator of cytokinesis 9Dpp3: dipeptidyl-peptidase 3Dpyd: dihydropyrimidine dehydrogenaseDpysl3: dihydropyrimidinase-like 3Dpysl4: dihydropyrimidinase-like 4Drd1ip: calcyon neuron-specific vesicular proteinDrg1: developmentally regulated GTP binding protein 1Drpla: atrophin 1Dscam: Down syndrome cell adhesion moleculeDscr1l1: regulator of calcineurin 2Dtnb: dystrobrevin, betaDuox1: dual oxidase 1Dusp12: dual specificity phosphatase 12Dusp2: dual specificity phosphatase 2Dvl1: dishevelled, dsh homolog 1 (Drosophila)Dync1h1: dynein, cytoplasmic 1, heavy chain 1Dync1li2: dynein, cytoplasmic 1, light intermediate chain 2Dyx1c1: dyslexia susceptibility 1 candidate 1Eaf2: ELL associated factor 2Ecel1: endothelin converting enzyme-like 1Echdc1: enoyl Coenzyme A hydratase domain containing 1Ecm1: extracellular matrix protein 1Ecm2: extracellular matrix protein 2, female organ and adipocyte specificEdf1: endothelial differentiation-related factor 1Ednrb: endothelin receptor type BEef2: eukaryotic translation elongation factor 2Efcbp1: N-terminal EF-hand calcium binding protein 1Efemp2: EGF-containing fibulin-like extracellular matrix protein 2Efnb1: ephrin-B1Egf: epidermal growth factor (beta-urogastrone)Egfl3: multiple EGF-like-domains 6Egfr: epidermal growth factor receptor (erythroblastic leukemia viral (v-erb-b) oncogene homolog, avian)Ehd2: EH-domain containing 2Ehd4: EH-domain containing 4Eif2c2: eukaryotic translation initiation factor 2C, 2Eif5b: eukaryotic translation initiation factor 5BElac2: elaC homolog 2 (E. coli)Elavl3: ELAV (embryonic lethal, abnormal vision, Drosophila)-like 3 (Hu antigen C)ELK1: ELK1, member of ETS oncogene familyElmo1: engulfment and cell motility 1Emb: embigin homolog (mouse)Emd: emerinEml5: echinoderm microtubule associated protein like 5Enah: enabled homolog (Drosophila)Enc1: ectodermal-neural cortex (with BTB-like domain)Eno2: enolase 2 (gamma, neuronal)Eno3: enolase 3 (beta, muscle)Enpp2: ectonucleotide pyrophosphatase/phosphodiesterase 2Enpp3: ectonucleotide pyrophosphatase/phosphodiesterase 3Enpp5: ectonucleotide pyrophosphatase/phosphodiesterase 5 (putative function)Ensa: endosulfine alphaEntpd2: ectonucleoside triphosphate diphosphohydrolase 2Entpd8: ectonucleoside triphosphate diphosphohydrolase 8Epha3: EPH receptor A3Epha5: EPH receptor A5Epha7: EPH receptor A7Ephb3: EPH receptor B3Ephx1: epoxide hydrolase 1, microsomal (xenobiotic)Epn1: epsin 1Eprs: glutamyl-prolyl-tRNA synthetaseEps8l1: EPS8-like 1Erap1: endoplasmic reticulum aminopeptidase 1Erbb3: v-erb-b2 erythroblastic leukemia viral oncogene homolog 3 (avian)Erbb4: v-erb-a erythroblastic leukemia viral oncogene homolog 4 (avian)Ercc5: excision repair cross-complementing rodent repair deficiency, complementation group 5Erp29: endoplasmic reticulum protein 29Esd: esterase D/formylglutathione hydrolaseEsr2: estrogen receptor 2 (ER beta)Etfb: electron-transfer-flavoprotein, beta polypeptideEts1: v-ets erythroblastosis virus E26 oncogene homolog 1 (avian)Evl: Enah/Vasp-likeExoc5: exocyst complex component 5Exoc7: exocyst complex component 7Ezr: ezrinFabp1: fatty acid binding protein 1, liverFabp2: fatty acid binding protein 2, intestinalFabp3: fatty acid binding protein 3, muscle and heart (mammary-derived growth inhibitor)Fabp4: fatty acid binding protein 4, adipocyteFabp7: fatty acid binding protein 7, brainFads1: fatty acid desaturase 1Fads2: fatty acid desaturase 2Faim: Fas apoptotic inhibitory moleculeFancd2: Fanconi anemia, complementation group D2Faslg: Fas ligand (TNF superfamily, member 6)Fasn: fatty acid synthaseFat: FAT tumor suppressor homolog 1 (Drosophila)Fat3: FAT tumor suppressor homolog 3 (Drosophila)Fbn1: fibrillin 1Fbn2: fibrillin 2Fbxw11: F-box and WD repeat domain containing 11Fetub: fetuin BFGA: fibrinogen alpha chainFgb: fibrinogen beta chainFgf18: fibroblast growth factor 18Fgf23: fibroblast growth factor 23Fgfr1: fibroblast growth factor receptor 1Fgfr1op2: FGFR1 oncogene partner 2Fgfr2: fibroblast growth factor receptor 2Fgfr3: fibroblast growth factor receptor 3Fhl1: four and a half LIM domains 1Fignl1: fidgetin-like 1Fip1l1: FIP1 like 1 (S. cerevisiae)Fkbp14: FK506 binding protein 14, 22 kDaFkbp1b: FK506 binding protein 1B, 12.6 kDaFkbp5: FK506 binding protein 5Flg: filaggrinFlii: flightless I homolog (Drosophila)Fmo3: flavin containing monooxygenase 3Fnta: farnesyltransferase, CAAX box, alphaFos: FBJ murine osteosarcoma viral oncogene homologFpgt: fucose-1-phosphate guanylyltransferaseFreq: frequenin homolog (Drosophila)Fshr: follicle stimulating hormone receptorFthfd: aldehyde dehydrogenase 1 family, member L1Fuca1: fucosidase, alpha-L-1, tissuefut10: fucosyltransferase 10 (alpha (1,3) fucosyltransferase)Fxc1: fracture callus 1 homolog (rat)Fxyd6: FXYD domain containing ion transport regulator 6Fzd9: frizzled homolog 9 (Drosophila)Gaa: glucosidase, alpha; acidGabarap: GABA(A) receptor-associated proteinGabarapl2: GABA(A) receptor-associated protein-like 2Gabbr1: gamma-aminobutyric acid (GABA) B receptor, 1Gabra3: gamma-aminobutyric acid (GABA) A receptor, alpha 3Gabrg2: gamma-aminobutyric acid (GABA) A receptor, gamma 2Gabrr3: gamma-aminobutyric acid (GABA) receptor, rho 3Gadd45a: growth arrest and DNA-damage-inducible, alphaGalc: galactosylceramidaseGalk1: galactokinase 1Galt: galactose-1-phosphate uridylyltransferaseGapdh: glyceraldehyde-3-phosphate dehydrogenaseGars: glycyl-tRNA synthetaseGas6: growth arrest-specific 6Gas7: growth arrest-specific 7Gata2: GATA binding protein 2Gata3: GATA binding protein 3GC: group-specific component (vitamin D binding protein)Gc: group-specific component (vitamin D binding protein)Gcgr: glucagon receptorGckr: glucokinase (hexokinase 4) regulatorGclc: glutamate-cysteine ligase, catalytic subunitGcnt3: glucosaminyl (N-acetyl) transferase 3, mucin typeGdap2: ganglioside induced differentiation associated protein 2Gdi1: GDP dissociation inhibitor 1Gdi2: GDP dissociation inhibitor 2Gfap: glial fibrillary acidic proteinGfpt2: glutamine-fructose-6-phosphate transaminase 2Gfra1: GDNF family receptor alpha 1Gfra3: GDNF family receptor alpha 3Ggt1: gamma-glutamyltransferase 1Ggtl3: gamma-glutamyltransferase 7Ggtla1: gamma-glutamyltransferase 5Ghitm: growth hormone inducible transmembrane proteinGif: gastric intrinsic factor (vitamin B synthesis)Gipc1: GIPC PDZ domain containing family, member 1Git1: G protein-coupled receptor kinase interacting ArfGAP 1Gja1: gap junction protein, alpha 1, 43 kDaGja10: gap junction protein, alpha 10, 62 kDaGja4: gap junction protein, alpha 4, 37 kDaGjb6: gap junction protein, beta 6, 30 kDaGla: galactosidase, alphaGldc: glycine dehydrogenase (decarboxylating)Glg1: golgi apparatus protein 1Gli: GLI family zinc finger 1Glo1: glyoxalase IGlra2: glycine receptor, alpha 2Glrx2: glutaredoxin 2Glud1: glutamate dehydrogenase 1Glul: glutamate-ammonia ligase (glutamine synthetase)Gm2a: GM2 ganglioside activatorGmcl1: germ cell-less homolog 1 (Drosophila)Gmfb: glia maturation factor, betaGmfg: glia maturation factor, gammaGmpr2: guanosine monophosphate reductase 2Gng7: guanine nucleotide binding protein (G protein), gamma 7Gnpat: glyceronephosphate O-acyltransferaseGns: glucosamine (N-acetyl)-6-sulfataseGolga2: golgi autoantigen, golgin subfamily a, 2Golgb1: golgin B1, golgi integral membrane proteinGolph3: golgi phosphoprotein 3 (coat-protein)Golph4: golgi integral membrane protein 4Gosr2: golgi SNAP receptor complex member 2Got1: glutamic-oxaloacetic transaminase 1, soluble (aspartate aminotransferase 1)Got2: glutamic-oxaloacetic transaminase 2, mitochondrial (aspartate aminotransferase 2)Gpam: glycerol-3-phosphate acyltransferase, mitochondrialGpc2: glypican 2Gpi: glucose phosphate isomeraseGpm6a: glycoprotein M6AGpr116: G protein-coupled receptor 116Gpr141: G protein-coupled receptor 141Gprc6a: G protein-coupled receptor, family C, group 6, member AGpsm1: G-protein signaling modulator 1 (AGS3-like, C. elegans)Gpt: glutamic-pyruvate transaminase (alanine aminotransferase)Gramd1a: GRAM domain containing 1AGrasp: GRP1 (general receptor for phosphoinositides 1)-associated scaffold proteinGrem1: gremlin 1, cysteine knot superfamily, homolog (Xenopus laevis)Gria1: glutamate receptor, ionotropic, AMPA 1Grid2: glutamate receptor, ionotropic, delta 2Grik1: glutamate receptor, ionotropic, kainate 1Grik4: glutamate receptor, ionotropic, kainate 4Grin2a: glutamate receptor, ionotropic, N-methyl D-aspartate 2AGrin2b: glutamate receptor, ionotropic, N-methyl D-aspartate 2BGrip1: glutamate receptor interacting protein 1Gripap1: GRIP1 associated protein 1Grk4: G protein-coupled receptor kinase 4Grk5: G protein-coupled receptor kinase 5Grk6: G protein-coupled receptor kinase 6Grm4: glutamate receptor, metabotropic 4Grm5: glutamate receptor, metabotropic 5Grpel1: GrpE-like 1, mitochondrial (E. coli)Gstk1: glutathione S-transferase kappa 1Gstm2: glutathione S-transferase mu 2 (muscle)Gsto1: glutathione S-transferase omega 1Gtf2ird1: GTF2I repeat domain containing 1Gtpbp4: GTP binding protein 4Gucy1a2: guanylate cyclase 1, soluble, alpha 2Gucy1a3: guanylate cyclase 1, soluble, alpha 3Gucy1b2: guanylate cyclase 1, soluble, beta 2Gucy2d: guanylate cyclase 2D, membrane (retina-specific)Gulp1: GULP, engulfment adaptor PTB domain containing 1Haao: 3-hydroxyanthranilate 3,4-dioxygenaseItpka: inositol 1,4,5-trisphosphate 3-kinase AKhdrbs2: KH domain containing, RNA binding, signal transduction associated 2Kpnb1: karyopherin (importin) beta 1Lamp2: lysosomal-associated membrane protein 2Ncstn: nicastrinNedd4l: neural precursor cell expressed, developmentally down-regulated 4-likeNip7: nuclear import 7 homolog (S. cerevisiae)Nnat: neuronatinNos1: nitric oxide synthase 1 (neuronal)Nox1: NADPH oxidase 1Npepps: aminopeptidase puromycin sensitiveNr1h3: nuclear receptor subfamily 1, group H, member 3Nr1i2: nuclear receptor subfamily 1, group I, member 2Nr6a1: nuclear receptor subfamily 6, group A, member 1Nrcam: neuronal cell adhesion moleculeNrd1: nardilysin (N-arginine dibasic convertase)Ntn1: netrin 1Nucb2: nucleobindin 2Nudc: nuclear distribution gene C homolog (A. nidulans)Nup35: nucleoporin 35 kDaNup54: nucleoporin 54 kDaNup98: nucleoporin 98 kDaOaz1: ornithine decarboxylase antizyme 1Ocrl: oculocerebrorenal syndrome of LoweOit3: oncoprotein induced transcript 3Olfm2: olfactomedin 2Opa1: optic atrophy 1 (autosomal dominant)Oplah: 5-oxoprolinase (ATP-hydrolysing)Oprd1: opioid receptor, delta 1Orc4l: origin recognition complex, subunit 4-like (yeast)Osmr: oncostatin M receptorOxr1: oxidation resistance 1P2rx7: purinergic receptor P2X, ligand-gated ion channel, 7P4hb: prolyl 4-hydroxylase, beta polypeptidePa2g4: proliferation-associated 2G4, 38 kDaPabpc4: poly(A) binding protein, cytoplasmic 4 (inducible form)Pace4: proprotein convertase subtilisin/kexin type 6Pacs1: phosphofurin acidic cluster sorting protein 1Pafah1b2: platelet-activating factor acetylhydrolase, isoform Ib, subunit 2 (30 kDa)Pafah1b3: platelet-activating factor acetylhydrolase, isoform Ib, subunit 3 (29 kDa)Pak1: p21 protein (Cdc42/Rac)-activated kinase 1Pak2: p21 protein (Cdc42/Rac)-activated kinase 2Pak3: p21 protein (Cdc42/Rac)-activated kinase 3Palm: paralemminPamci: Ras association (RalGDS/AF-6) domain family (N-terminal) member 9Panx1: pannexin 1Panx2: pannexin 2Pard3: par-3 partitioning defective 3 homolog (C. elegans)Parg: poly (ADP-ribose) glycohydrolasePark7: Parkinson disease (autosomal recessive, early onset) 7Pawr: PRKC, apoptosis, WT1, regulatorPax3: paired box 3Pbp: phosphatidylethanolamine binding protein 1Pc: pyruvate carboxylasePcca: propionyl Coenzyme A carboxylase, alpha polypeptidePcdh21: protocadherin 21Pcdh7: protocadherin 7Pcdha3: protocadherin alpha 3Pcdhb1: protocadherin beta 1Pck1: phosphoenolpyruvate carboxykinase 1 (soluble)Pclo: piccolo (presynaptic cytomatrix protein)Pcm1: pericentriolar material 1Pcmt1: protein-L-isoaspartate (D-aspartate) O-methyltransferasePCNT: pericentrinPcnx: pecanex homolog (Drosophila)Pcnxl3: pecanex-like 3 (Drosophila)Pcsk1: proprotein convertase subtilisin/kexin type 1Pcsk1n: proprotein convertase subtilisin/kexin type 1 inhibitorPcsk5: proprotein convertase subtilisin/kexin type 5Pcyox1: prenylcysteine oxidase 1Pcyt1b: phosphate cytidylyltransferase 1, choline, betaPdap1: PDGFA associated protein 1Pdc: phosducinPdcd2: programmed cell death 2Pdcl: phosducin-likePde10a: phosphodiesterase 10APde1a: phosphodiesterase 1A, calmodulin-dependentPde1c: phosphodiesterase 1C, calmodulin-dependent 70 kDaPde4a: phosphodiesterase 4A, cAMP-specific (phosphodiesterase E2 dunce homolog, Drosophila)Pde4b: phosphodiesterase 4B, cAMP-specific (phosphodiesterase E4 dunce homolog, Drosophila)Pde4d: phosphodiesterase 4D, cAMP-specific (phosphodiesterase E3 dunce homolog, Drosophila)Pde5a: phosphodiesterase 5A, cGMP-specificPde7a: phosphodiesterase 7APde7b: phosphodiesterase 7BPdgfra: platelet-derived growth factor receptor, alpha polypeptidePdhb: pyruvate dehydrogenase (lipoamide) betaPdia3: protein disulfide isomerase family A, member 3Pdia4: protein disulfide isomerase family A, member 4Pdk4: pyruvate dehydrogenase kinase, isozyme 4Pdlim7: PDZ and LIM domain 7 (enigma)Pds5b: PDS5, regulator of cohesion maintenance, homolog B (S. cerevisiae)Pdzd3: PDZ domain containing 3Pepd: peptidase DPer3: period homolog 3 (Drosophila)Pex14: peroxisomal biogenesis factor 14Pfkl: phosphofructokinase, liverPfkm: phosphofructokinase, musclePfkp: phosphofructokinase, plateletPgam1: phosphoglycerate mutase 1 (brain)PGAP1: post-GPI attachment to proteins 1Pgd: phosphogluconate dehydrogenasePgf: placental growth factorPgk1: phosphoglycerate kinase 1Pgm1: phosphoglucomutase 1Pgr: progesterone receptorPgrmc1: progesterone receptor membrane component 1Phactr1: phosphatase and actin regulator 1Phactr3: phosphatase and actin regulator 3Phb: prohibitinPhex: phosphate regulating endopeptidase homolog, X-linkedPhgdh: phosphoglycerate dehydrogenasePhip: pleckstrin homology domain interacting proteinPhtf1: putative homeodomain transcription factor 1Phyhipl: phytanoyl-CoA 2-hydroxylase interacting protein-likePi4ka: phosphatidylinositol 4-kinase, catalytic, alphaPicalm: phosphatidylinositol binding clathrin assembly proteinPigq: phosphatidylinositol glycan anchor biosynthesis, class QPigs: phosphatidylinositol glycan anchor biosynthesis, class SPik3cg: phosphoinositide-3-kinase, catalytic, gamma polypeptidePip5k1a: phosphatidylinositol-4-phosphate 5-kinase, type I, alphaPip5k1c: phosphatidylinositol-4-phosphate 5-kinase, type I, gammaPip5k2a: phosphatidylinositol-5-phosphate 4-kinase, type II, alphaPip5k2c: phosphatidylinositol-5-phosphate 4-kinase, type II, gammaPipox: pipecolic acid oxidasePitpn: phosphatidylinositol transfer protein, alphaPkd1: polycystic kidney disease 1 (autosomal dominant)Pkia: protein kinase (cAMP-dependent, catalytic) inhibitor alphaPkm2: pyruvate kinase, musclePla2g4c: phospholipase A2, group IVC (cytosolic, calcium-independent)Plaa: phospholipase A2-activating proteinPlau: plasminogen activator, urokinasePlcb1: phospholipase C, beta 1 (phosphoinositide-specific)Plcl1: phospholipase C-like 1Pld3: phospholipase D family, member 3Plekha4: pleckstrin homology domain containing, family A (phosphoinositide binding specific) member 4Plekhe1: PH domain and leucine rich repeat protein phosphatase 1Plekhm1: pleckstrin homology domain containing, family M (with RUN domain) member 1Plg: plasminogenPlk1: polo-like kinase 1 (Drosophila)Plrg1: pleiotropic regulator 1 (PRL1 homolog, Arabidopsis)Plunc: palate, lung and nasal epithelium associatedPlvap: plasmalemma vesicle associated proteinPlxnb2: plexin B2Pmpca: peptidase (mitochondrial processing) alphaPmvk: phosphomevalonate kinasePnliprp2: pancreatic lipase-related protein 2Pnma1: paraneoplastic antigen MA1Pno1: partner of NOB1 homolog (S. cerevisiae)Pnpla2: patatin-like phospholipase domain containing 2Pofut1: protein O-fucosyltransferase 1Pon2: paraoxonase 2Pon3: paraoxonase 3Pop7: processing of precursor 7, ribonuclease P/MRP subunit (S. cerevisiae)Por: P450 (cytochrome) oxidoreductasePou2f2: POU class 2 homeobox 2Ppfia3: protein tyrosine phosphatase, receptor type, f polypeptide (PTPRF), interacting protein, alpha 3Ppgb: cathepsin APpib: peptidylprolyl isomerase B (cyclophilin B)Ppid: peptidylprolyl isomerase DPpil3: peptidylprolyl isomerase (cyclophilin)-like 3Ppm2c: pyruvate dehydrogenase phosphatase catalytic subunit 1Ppp1r10: protein phosphatase 1, regulatory (inhibitor) subunit 10Ppp1r14b: protein phosphatase 1, regulatory (inhibitor) subunit 14BPpp1r14d: protein phosphatase 1, regulatory (inhibitor) subunit 14DPpp1r1a: protein phosphatase 1, regulatory (inhibitor) subunit 1APpp1r7: protein phosphatase 1, regulatory (inhibitor) subunit 7Ppp1r8: protein phosphatase 1, regulatory (inhibitor) subunit 8Ppp1r9a: protein phosphatase 1, regulatory (inhibitor) subunit 9APpp1r9b: protein phosphatase 1, regulatory (inhibitor) subunit 9BPpp2cb: protein phosphatase 2 (formerly 2A), catalytic subunit, beta isoformPpp2r1a: protein phosphatase 2 (formerly 2A), regulatory subunit A, alpha isoformPpp2r1b: protein phosphatase 2 (formerly 2A), regulatory subunit A, beta isoformPpp2r2a: protein phosphatase 2 (formerly 2A), regulatory subunit B, alpha isoformPPP2R2B: protein phosphatase 2 (formerly 2A), regulatory subunit B, beta isoformPpp2r5e: protein phosphatase 2, regulatory subunit B', epsilon isoformPpp3cc: protein phosphatase 3 (formerly 2B), catalytic subunit, gamma isoformPpp5c: protein phosphatase 5, catalytic subunitPrdm4: PR domain containing 4Prdx1: peroxiredoxin 1Prep: prolyl endopeptidasePrf1: perforin 1 (pore forming protein)Prkaa2: protein kinase, AMP-activated, alpha 2 catalytic subunitPrkaca: protein kinase, cAMP-dependent, catalytic, alphaprkar1a: protein kinase, cAMP-dependent, regulatory, type I, alpha (tissue specific extinguisher 1)Prkar1a: protein kinase, cAMP-dependent, regulatory, type I, alpha (tissue specific extinguisher 1)Prkar2a: protein kinase, cAMP-dependent, regulatory, type II, alphaPrkar2b: protein kinase, cAMP-dependent, regulatory, type II, betaPrkca: protein kinase C, alphaPrkcb1: protein kinase C, betaPrkci: protein kinase C, iotaPrkcm: protein kinase D1PRKCQ: protein kinase C, thetaPrkcz: protein kinase C, zetaPrkwnk1: WNK lysine deficient protein kinase 1Prmt3: protein arginine methyltransferase 3Prnp: prion proteinProm2: prominin 2Prph2: peripherin 2 (retinal degeneration, slow)Prpsap1: phosphoribosyl pyrophosphate synthetase-associated protein 1Prpsap2: phosphoribosyl pyrophosphate synthetase-associated protein 2Prr3: proline rich 3Prrx2: paired related homeobox 2Prrxl1: dorsal root ganglia homeoboxPrss1: protease, serine, 1 (trypsin 1)Prss12: protease, serine, 12 (neurotrypsin, motopsin)Prss15: lon peptidase 1, mitochondrialPrtg: protogenin homolog (Gallus gallus)Prx: periaxinPsat1: phosphoserine aminotransferase 1Psd: pleckstrin and Sec7 domain containingPsd4: pleckstrin and Sec7 domain containing 4Psmc1: proteasome (prosome, macropain) 26S subunit, ATPase, 1Psmc3: proteasome (prosome, macropain) 26S subunit, ATPase, 3Psmc5: proteasome (prosome, macropain) 26S subunit, ATPase, 5Psmd1: proteasome (prosome, macropain) 26S subunit, non-ATPase, 1Psme1: proteasome (prosome, macropain) activator subunit 1 (PA28 alpha)Psme2: proteasome (prosome, macropain) activator subunit 2 (PA28 beta)Psme3: proteasome (prosome, macropain) activator subunit 3 (PA28 gamma; Ki)Psph: phosphoserine phosphatasePtbp1: polypyrimidine tract binding protein 1Ptbp2: polypyrimidine tract binding protein 2Ptger2: prostaglandin E receptor 2 (subtype EP2), 53 kDaPtgis: prostaglandin I2 (prostacyclin) synthasePtgs1: prostaglandin-endoperoxide synthase 1 (prostaglandin G/H synthase and cyclooxygenase)Pth: parathyroid hormonePthr2: parathyroid hormone 2 receptorPtk2: PTK2 protein tyrosine kinase 2Ptn: pleiotrophinPtov1: prostate tumor overexpressed 1Ptp4a1: protein tyrosine phosphatase type IVA, member 1Ptpn11: protein tyrosine phosphatase, non-receptor type 11Rnmt: RNA (guanine-7-) methyltransferaseRraga: Ras-related GTP binding ARtn4: reticulon 4Ryr3: ryanodine receptor 3Sca1: ataxin 1Sca10: ataxin 10Scfd1: sec1 family domain containing 1Scgb3a2: secretoglobin, family 3A, member 2Scn1a: sodium channel, voltage-gated, type I, alpha subunitScn2a1: sodium channel, voltage-gated, type II, alpha subunitScp2: sterol carrier protein 2Sdad1: SDA1 domain containing 1Sdc2: syndecan 2Sdcbp: syndecan binding protein (syntenin)Sdfr1: neuroplastinSdha: succinate dehydrogenase complex, subunit A, flavoprotein (Fp)Sec11l3: SEC11 homolog C (S. cerevisiae)Sec31l1: SEC31 homolog A (S. cerevisiae)Sectm1: secreted and transmembrane 1Sema6c: sema domain, transmembrane domain (TM), and cytoplasmic domain, (semaphorin) 6CSephs1: selenophosphate synthetase 1Serinc3: serine incorporator 3Serpinb3: serpin peptidase inhibitor, clade B (ovalbumin), member 3Serpine2: serpin peptidase inhibitor, clade E (nexin, plasminogen activator inhibitor type 1), member 2Sez6: seizure related 6 homolog (mouse)Sf3b1: splicing factor 3b, subunit 1, 155 kDaSfpq: splicing factor proline/glutamine-rich (polypyrimidine tract binding protein associated)Sfrp4: secreted frizzled-related protein 4Sfrs10: transformer 2 beta homolog (Drosophila)Sfrs8: splicing factor, arginine/serine-rich 8 (suppressor-of-white-apricot homolog, Drosophila)Sfrs9: splicing factor, arginine/serine-rich 9Sftpb: surfactant protein BSfxn3: sideroflexin 3Sfxn5: sideroflexin 5Sgca: sarcoglycan, alpha (50 kDa dystrophin-associated glycoprotein)Sgtb: small glutamine-rich tetratricopeptide repeat (TPR)-containing, betaSh2d4a: SH2 domain containing 4ASh3bp4: SH3-domain binding protein 4Sh3bp5: SH3-domain binding protein 5 (BTK-associated)Sh3gl3: SH3-domain GRB2-like 3Sh3glb2: SH3-domain GRB2-like endophilin B2Shank1: SH3 and multiple ankyrin repeat domains 1Shank2: SH3 and multiple ankyrin repeat domains 2Shc1: SHC (Src homology 2 domain containing) transforming protein 1Shh: sonic hedgehog homolog (Drosophila)Shoc2: soc-2 suppressor of clear homolog (C. elegans)Siat7A: ST6 (alpha-N-acetyl-neuraminyl-2,3-beta-galactosyl-1,3)-N-acetylgalactosaminide alpha-2,6-sialyltransferase 1Sipa1: signal-induced proliferation-associated 1Sipa1l2: signal-induced proliferation-associated 1 like 2Sipa1l3: signal-induced proliferation-associated 1 like 3Sirpa: signal-regulatory protein alphaSirt2: sirtuin (silent mating type information regulation 2 homolog) 2 (S. cerevisiae)Sirt5: sirtuin (silent mating type information regulation 2 homolog) 5 (S. cerevisiae)Slc11a2: solute carrier family 11 (proton-coupled divalent metal ion transporters), member 2Slc12a1: solute carrier family 12 (sodium/potassium/chloride transporters), member 1Slc12a5: solute carrier family 12 (potassium-chloride transporter), member 5Slco3a1: solute carrier organic anion transporter family, member 3A1Slit1: slit homolog 1 (Drosophila)Slit2: slit homolog 2 (Drosophila)Slit3: slit homolog 3 (Drosophila)Slk: STE20-like kinase (yeast)Slu7: SLU7 splicing factor homolog (S. cerevisiae)Smad1: SMAD family member 1Smarca2: SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 2Smc1l1: structural maintenance of chromosomes 1ASmo: smoothened homolog (Drosophila)Smoc1: SPARC related modular calcium binding 1Smu1: smu-1 suppressor of mec-8 and unc-52 homolog (C. elegans)Sn: sialic acid binding Ig-like lectin 1, sialoadhesinSnai1: snail homolog 1 (Drosophila)Snai2: snail homolog 2 (Drosophila)Snap23: synaptosomal-associated protein, 23 kDaSnap25: synaptosomal-associated protein, 25 kDaSnap91: synaptosomal-associated protein, 91 kDa homolog (mouse)Snca: synuclein, alpha (non A4 component of amyloid precursor)Sncb: synuclein, betaSnd1: staphylococcal nuclease and tudor domain containing 1Snph: syntaphilinSnrk: SNF related kinaseSnx17: sorting nexin 17Snx25: sorting nexin 25Snx3: sorting nexin 3Soat1: sterol O-acyltransferase 1Socs1: suppressor of cytokine signaling 1SOD1: superoxide dismutase 1, solubleSod2: superoxide dismutase 2, mitochondrialSord: sorbitol dehydrogenaseSox10: SRY (sex determining region Y)-box 10Sp2: Sp2 transcription factorSparc: secreted protein, acidic, cysteine-rich (osteonectin)Spata20: spermatogenesis associated 20Spint1: serine peptidase inhibitor, Kunitz type 1Spp1: secreted phosphoprotein 1Spsb4: splA/ryanodine receptor domain and SOCS box containing 4Sqle: squalene epoxidaseSrc: v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog (avian)Srd5a2: steroid-5-alpha-reductase, alpha polypeptide 2Srebf1: sterol regulatory element binding transcription factor 1Srprb: signal recognition particle receptor, B subunitSsb: Sjogren syndrome antigen B (autoantigen La)Ssr4: signal sequence receptor, delta (translocon-associated protein delta)Ssrp1: structure specific recognition protein 1Sstr2: somatostatin receptor 2Ssx2ip: synovial sarcoma, X breakpoint 2 interacting proteinSt14: suppression of tumorigenicity 14 (colon carcinoma)St18: suppression of tumorigenicity 18 (breast carcinoma) (zinc finger protein)St3gal1: ST3 beta-galactoside alpha-2,3-sialyltransferase 1St6gal2: ST6 beta-galactosamide alpha-2,6-sialyltransferase 2St7: suppression of tumorigenicity 7St7l: suppression of tumorigenicity 7 likeStar: steroidogenic acute regulatory proteinStard3nl: STARD3 N-terminal likeStat1: signal transducer and activator of transcription 1, 91 kDaStat3: signal transducer and activator of transcription 3 (acute-phase response factor)Stau1: staufen, RNA binding protein, homolog 1 (Drosophila)Stch: heat shock protein 70 kDa family, member 13Ste: sulfotransferase family 1E, estrogen-preferring, member 1Stim2: stromal interaction molecule 2Stip1: stress-induced-phosphoprotein 1Stk10: serine/threonine kinase 10Stk11: serine/threonine kinase 11Stmn1: stathmin 1Stmn2: stathmin-like 2Stmn3: stathmin-like 3Stmn4: stathmin-like 4Stnl: eukaryotic translation elongation factor 1 alpha 2Stom: stomatinStrbp: spermatid perinuclear RNA binding proteinStrn: striatin, calmodulin binding proteinStx12: syntaxin 12Stx1a: syntaxin 1A (brain)Stx4a: syntaxin 4Stx5a: syntaxin 5Stx6: syntaxin 6Stx8: syntaxin 8Stxbp3: syntaxin binding protein 3Stxbp5: syntaxin binding protein 5 (tomosyn)Suclg1: succinate-CoA ligase, alpha subunitSult1a1: sulfotransferase family, cytosolic, 1A, phenol-preferring, member 1Sult1c1: sulfotransferase family, cytosolic, 1C, member 2Sult1c2: sulfotransferase family, cytosolic, 1C, member 2Sult1e1: sulfotransferase family 1E, estrogen-preferring, member 1Sult4a1: sulfotransferase family 4A, member 1Supv3l1: suppressor of var1, 3-like 1 (S. cerevisiae)Surf6: surfeit 6Suv420h2: suppressor of variegation 4-20 homolog 2 (Drosophila)Sv2a: synaptic vesicle glycoprotein 2ASv2b: synaptic vesicle glycoprotein 2BSycp1: synaptonemal complex protein 1Sycp2: synaptonemal complex protein 2Syn1: synapsin ISyn2: synapsin IISyn3: synapsin IIISyngap1: synaptic Ras GTPase activating protein 1 homolog (rat)Synj1: synaptojanin 1Synj2: synaptojanin 2Synj2bp: synaptojanin 2 binding proteinSynpo: synaptopodinSypl: synaptophysin-like 1Syt11: synaptotagmin XISyt12: synaptotagmin XIISyt5: synaptotagmin VSyt6: synaptotagmin VISyt8: synaptotagmin VIIITacc1: transforming, acidic coiled-coil containing protein 1Tacc2: transforming, acidic coiled-coil containing protein 2Tacr1: tachykinin receptor 1Taf1c: TATA box binding protein (TBP)-associated factor, RNA polymerase I, C, 110 kDaTaf9l: TAF9B RNA polymerase II, TATA box binding protein (TBP)-associated factor, 31 kDaTagln: transgelinTagln3: transgelin 3Taldo1: transaldolase 1Taok1: TAO kinase 1Tapbp: TAP binding protein (tapasin)Tars: threonyl-tRNA synthetaseTas2r41: taste receptor, type 2, member 41Tat: tyrosine aminotransferaseTax1bp1: Tax1 (human T-cell leukemia virus type I) binding protein 1Tbc1d10b: TBC1 domain family, member 10BTbca: tubulin folding cofactor ATbx2: T-box 2Tcirg1: T-cell, immune regulator 1, ATPase, H+ transporting, lysosomal V0 subunit A3Tcn2: transcobalamin II; macrocytic anemiaTcp1: t-complex 1Tcra: T cell receptor alpha locusTdg: thymine-DNA glycosylaseTdrd7: tudor domain containing 7Tead1: TEA domain family member 1 (SV40 transcriptional enhancer factor)Tegt: transmembrane BAX inhibitor motif containing 6Tg: thyroglobulinTgfb1: transforming growth factor, beta 1Tgfbr3: transforming growth factor, beta receptor IIITgm1: transglutaminase 1 (K polypeptide epidermal type I, protein-glutamine-gamma-glutamyltransferase)Tgm2: transglutaminase 2 (C polypeptide, protein-glutamine-gamma-glutamyltransferase)Thbd: thrombomodulinThbs4: thrombospondin 4Thpo: thrombopoietinThra: thyroid hormone receptor, alpha (erythroblastic leukemia viral (v-erb-a) oncogene homolog, avian)Thrap3: thyroid hormone receptor associated protein 3Thrb: thyroid hormone receptor, beta (erythroblastic leukemia viral (v-erb-a) oncogene homolog 2, avian)Thy1: Thy-1 cell surface antigenTigd3: tigger transposable element derived 3Timm44: translocase of inner mitochondrial membrane 44 homolog (yeast)Timm8a: translocase of inner mitochondrial membrane 8 homolog A (yeast)Tinag: tubulointerstitial nephritis antigenTjp1: tight junction protein 1 (zona occludens 1)Tjp2: tight junction protein 2 (zona occludens 2)Tkt: transketolaseTle3: transducin-like enhancer of split 3 (E(sp1) homolog, Drosophila)Tlr3: toll-like receptor 3Tlr4: toll-like receptor 4Tlr5: toll-like receptor 5Tlr6: toll-like receptor 6Tlr9: toll-like receptor 9Tm4sf8: tetraspanin 3Tm9sf2: transmembrane 9 superfamily member 2Tm9sf3: transmembrane 9 superfamily member 3Tmco1: transmembrane and coiled-coil domains 1Tmeff1: transmembrane protein with EGF-like and two follistatin-like domains 1Tmem27: transmembrane protein 27Tmf1: TATA element modulatory factor 1Tmpo: thymopoietinTmsb10: thymosin beta 10Tnfaip1: tumor necrosis factor, alpha-induced protein 1 (endothelial)Tnni1: troponin I type 1 (skeletal, slow)Tnni2: troponin I type 2 (skeletal, fast)Tnnt3: troponin T type 3 (skeletal, fast)Tob1: transducer of ERBB2, 1Tob2: transducer of ERBB2, 2Tom1: target of myb1 (chicken)Tor3a: torsin family 3, member ATpbg: trophoblast glycoproteinTpd52l2: tumor protein D52-like 2Tph2: tryptophan hydroxylase 2Tpm3: tropomyosin 3Tpo: thyroid peroxidaseTpst2: tyrosylprotein sulfotransferase 2Tpt1: tumor protein, translationally-controlled 1Tr4: nuclear receptor subfamily 2, group C, member 2Traf3ip1: TNF receptor-associated factor 3 interacting protein 1Trak2: trafficking protein, kinesin binding 2Trap1: TNF receptor-associated protein 1Trib3: tribbles homolog 3 (Drosophila)Trim13: tripartite motif-containing 13Trim54: tripartite motif-containing 54Trip10: thyroid hormone receptor interactor 10Trpc2: transient receptor potential cation channel, subfamily C, member 2 (pseudogene)Trpc4: transient receptor potential cation channel, subfamily C, member 4Trpc5: transient receptor potential cation channel, subfamily C, member 5Trpc7: transient receptor potential cation channel, subfamily C, member 7Trpv1: transient receptor potential cation channel, subfamily V, member 1Trpv4: transient receptor potential cation channel, subfamily V, member 4Tsc1: tuberous sclerosis 1Tsc2: tuberous sclerosis 2Tsg101: tumor susceptibility gene 101Tsga10: testis specific, 10Tsga10ip: testis specific, 10 interacting proteinTshr: thyroid stimulating hormone receptorTsn: translinTsnax: translin-associated factor XTst: thiosulfate sulfurtransferase (rhodanese)Ttc1: tetratricopeptide repeat domain 1Ttn: titinTub: tubby homolog (mouse)Tuba1a: tubulin, alpha 1aTubb2b: tubulin, beta 2BTubb2c: tubulin, beta 2CTubb3: tubulin, beta 3Tusc3: tumor suppressor candidate 3Txn: thioredoxinTxn2: thioredoxin 2Txndc4: endoplasmic reticulum protein 44Txnip: thioredoxin interacting proteinTxnl2: glutaredoxin 3Txnrd1: thioredoxin reductase 1Txnrd2: thioredoxin reductase 2Ubc: ubiquitin CUbe2e2: ubiquitin-conjugating enzyme E2E 2 (UBC4/5 homolog, yeast)Ubl3: ubiquitin-like 3Ubqln1: ubiquilin 1Ubxd3: UBX domain protein 10Uchl1: ubiquitin carboxyl-terminal esterase L1 (ubiquitin thiolesterase)Ucp1: uncoupling protein 1 (mitochondrial, proton carrier)Ucp2: uncoupling protein 2 (mitochondrial, proton carrier)Ugt1a1: UDP glucuronosyltransferase 1 family, polypeptide A1Umod: uromodulinUnc13a: unc-13 homolog A (C. elegans)Unc13b: unc-13 homolog B (C. elegans)Unc13c: unc-13 homolog C (C. elegans)Unc5b: unc-5 homolog B (C. elegans)Uqcrc2: ubiquinol-cytochrome c reductase core protein IIUqcrfs1: ubiquinol-cytochrome c reductase, Rieske iron-sulfur polypeptide 1Uso1: USO1 homolog, vesicle docking protein (yeast)Usp11: ubiquitin specific peptidase 11Vamp1: vesicle-associated membrane protein 1 (synaptobrevin 1)Vamp2: vesicle-associated membrane protein 2 (synaptobrevin 2)Vamp3: vesicle-associated membrane protein 3 (cellubrevin)Vapa: VAMP (vesicle-associated membrane protein)-associated protein A, 33 kDaVapb: VAMP (vesicle-associated membrane protein)-associated protein B and CVCAN: versicanVcan: versicanVcp: valosin-containing proteinVcpip1: valosin containing protein (p97)/p47 complex interacting protein 1Vdac1: voltage-dependent anion channel 1Vdac2: voltage-dependent anion channel 2Vegfa: vascular endothelial growth factor AVgcnl1: sodium leak channel, non-selectiveVgf: VGF nerve growth factor inducibleVipr2: vasoactive intestinal peptide receptor 2Vpreb1: pre-B lymphocyte 1Vps33a: vacuolar protein sorting 33 homolog A (S. cerevisiae)Vps33b: vacuolar protein sorting 33 homolog B (yeast)Vps4a: vacuolar protein sorting 4 homolog A (S. cerevisiae)Vsnl1: visinin-like 1Vtn: vitronectinWars: tryptophanyl-tRNA synthetaseWbp2: WW domain binding protein 2Wdr10: intraflagellar transport 122 homolog (Chlamydomonas)Wdr44: WD repeat domain 44Wdr7: WD repeat domain 7Wfs1: Wolfram syndrome 1 (wolframin)Wif1: WNT inhibitory factor 1Wipf1: WAS/WASL interacting protein family, member 1Wnk4: WNK lysine deficient protein kinase 4Wnt5a: wingless-type MMTV integration site family, member 5AWnt7a: wingless-type MMTV integration site family, member 7AXkr6: XK, Kell blood group complex subunit-related family, member 6Xpnpep2: X-prolyl aminopeptidase (aminopeptidase P) 2, membrane-boundXpo1: exportin 1 (CRM1 homolog, yeast)Xpo6: exportin 6Xrcc1: X-ray repair complementing defective repair in Chinese hamster cells 1Xrcc5: X-ray repair complementing defective repair in Chinese hamster cells 5Xylt1: xylosyltransferase IYars2: tyrosyl-tRNA synthetase 2, mitochondrialYes1: v-yes-1 Yamaguchi sarcoma viral oncogene homolog 1Ykt6: YKT6 v-SNARE homolog (S. cerevisiae)Ywhab: tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, beta polypeptideYy1: YY1 transcription factorZnf382: zinc finger protein 382Zranb1: zinc finger, RAN-binding domain containing 1Zwint: ZW10 interactor.

B.

Lipid raft-derived extracted proteins from Alzheimer’s disease (3xTgAD) mouse 16-month-old cortical tissue. Specific proteins isolated from 3xTgAD mouse cortex were identified with multidimensional protein identification technology (MudPIT) LC MS/MS. Each protein was identified in at least two out of three experimental replicate animals and from at least two isolated peptides per protein. The following are the protein symbol and its corresponding definition.Abca1: ATP-binding cassette, sub-family A (ABC1), member 1ABCA7: ATP-binding cassette, sub-family A (ABC1), member 7Abcb4: ATP-binding cassette, sub-family B (MDR/TAP), member 4Abcc1: ATP-binding cassette, sub-family C (CFTR/MRP), member 1Abcc2: ATP-binding cassette, sub-family C (CFTR/MRP), member 2Abcc4: ATP-binding cassette, sub-family C (CFTR/MRP), member 4Abi1: abl-interactor 1Acadl: acyl-Coenzyme A dehydrogenase, long chainAcat1: acetyl-Coenzyme A acetyltransferase 1Acin1: apoptotic chromatin condensation inducer 1Acmsd: aminocarboxymuconate semialdehyde decarboxylaseAcp2: acid phosphatase 2, lysosomalActa1: actin, alpha 1, skeletal muscleActb: actin, betaActn4: actinin, alpha 4Acvr1: activin A receptor, type IAdam2: ADAM metallopeptidase domain 2Adam6: ADAM metallopeptidase domain 6 (pseudogene)Adcy1: adenylate cyclase 1 (brain)Adcy5: adenylate cyclase 5Adcy8: adenylate cyclase 8 (brain)Adcyap1: adenylate cyclase activating polypeptide 1 (pituitary)Adcyap1r1: adenylate cyclase activating polypeptide 1 (pituitary) receptor type IAdd1: adducin 1 (alpha)Add2: adducin 2 (beta)Adrbk1: adrenergic, beta, receptor kinase 1Aes: amino-terminal enhancer of splitAgpat1: 1-acylglycerol-3-phosphate O-acyltransferase 1 (lysophosphatidic acid acyltransferase, alpha)Agpat4: 1-acylglycerol-3-phosphate O-acyltransferase 4 (lysophosphatidic acid acyltransferase, delta)Agrn: agrinAhi1: Abelson helper integration site 1Ahr: aryl hydrocarbon receptorAhrr: aryl-hydrocarbon receptor repressorAk3: adenylate kinase 3Akap12: A kinase (PRKA) anchor protein 12Akap3: A kinase (PRKA) anchor protein 3Akap4: A kinase (PRKA) anchor protein 4Akap9: A kinase (PRKA) anchor protein (yotiao) 9Alad: aminolevulinate, delta-, dehydrataseAldh1a3: aldehyde dehydrogenase 1 family, member A3Alox5: arachidonate 5-lipoxygenaseAmpd1: adenosine monophosphate deaminase 1 (isoform M)Anxa3: annexin A3Anxa6: annexin A6Apex2: APEX nuclease (apurinic/apyrimidinic endonuclease) 2Apob: apolipoprotein B (including Ag(x) antigen)Apod: apolipoprotein DApp: amyloid beta (A4) precursor proteinAps: kallikrein-related peptidase 3Aqp3: aquaporin 3 (Gill blood group)Aqp4: aquaporin 4Aqp8: aquaporin 8Arf1: ADP-ribosylation factor 1Arf4: ADP-ribosylation factor 4Arf6: ADP-ribosylation factor 6Arfip1: ADP-ribosylation factor interacting protein 1Arhgap20: Rho GTPase activating protein 20Arhgap8: Rho GTPase activating protein 8Arhgdia: Rho GDP dissociation inhibitor (GDI) alphaArhgef11: Rho guanine nucleotide exchange factor (GEF) 11Arhgef12: Rho guanine nucleotide exchange factor (GEF) 12Arhgef6: Rac/Cdc42 guanine nucleotide exchange factor (GEF) 6Arnt: aryl hydrocarbon receptor nuclear translocatorArntl: aryl hydrocarbon receptor nuclear translocator-likeArpp19: cAMP-regulated phosphoprotein, 19 kDaAscc1: activating signal cointegrator 1 complex subunit 1Asz1: ankyrin repeat, SAM and basic leucine zipper domain containing 1Atcay: ataxia, cerebellar, Cayman typeAtf3: activating transcription factor 3Atm: ataxia telangiectasia mutatedAtp1a1: ATPase, Na+/K+ transporting, alpha 1 polypeptideAtp1a4: ATPase, Na+/K+ transporting, alpha 4 polypeptideAtp1b1: ATPase, Na+/K+ transporting, beta 1 polypeptideATP2B1: ATPase, Ca++ transporting, plasma membrane 1Atp2b1: ATPase, Ca++ transporting, plasma membrane 1Atp2b2: ATPase, Ca++ transporting, plasma membrane 2Atp5a1: ATP synthase, H+ transporting, mitochondrial F1 complex, alpha subunit 1, cardiac muscleAtp5b: ATP synthase, H+ transporting, mitochondrial F1 complex, beta polypeptideAtp5f1: ATP synthase, H+ transporting, mitochondrial F0 complex, subunit B1Atp5h: ATP synthase, H+ transporting, mitochondrial F0 complex, subunit dAtp5i: ATP synthase, H+ transporting, mitochondrial F0 complex, subunit EAtp5j: ATP synthase, H+ transporting, mitochondrial F0 complex, subunit F6Atp6b2: ATPase, H+ transporting, lysosomal 56/58 kDa, V1 subunit B2Atp6l: ATPase, H+ transporting, lysosomal 16 kDa, V0 subunit cAtp6v0a1: ATPase, H+ transporting, lysosomal V0 subunit a1ATPBD1C: GPN-loop GTPase 3Atxn3: ataxin 3Avil: advillinB3gat1: beta-1,3-glucuronyltransferase 1 (glucuronosyltransferase P)Bace1: beta-site APP-cleaving enzyme 1Basp1: brain abundant, membrane attached signal protein 1Bat2: HLA-B associated transcript 2Bat5: HLA-B associated transcript 5Bax: BCL2-associated X proteinBcl10: B-cell CLL/lymphoma 10Begain: brain-enriched guanylate kinase-associated homolog (rat)Bmp6: bone morphogenetic protein 6Bnip1: BCL2/adenovirus E1B 19 kDa interacting protein 1Bnip3: BCL2/adenovirus E1B 19 kDa interacting protein 3Bpnt1: 3^'(2^'), 5^'-bisphosphate nucleotidase 1Brd2: bromodomain containing 2Brd8: bromodomain containing 8Bst1: bone marrow stromal cell antigen 1Btg2: BTG family, member 2Bzrap1: benzodiazepine receptor (peripheral) associated protein 1c3orf6: coiled-coil domain containing 50C4a: complement component 4A (Rodgers blood group)c8b: complement component 8, beta polypeptideCabc1: chaperone, ABC1 activity of bc1 complex homolog (S. pombe)Cabin1: calcineurin binding protein 1Cacna1g: calcium channel, voltage-dependent, T type, alpha 1G subunitCacna2d1: calcium channel, voltage-dependent, alpha 2/delta subunit 1Cacna2d2: calcium channel, voltage-dependent, alpha 2/delta subunit 2Cacna2d3: calcium channel, voltage-dependent, alpha 2/delta subunit 3Cacnb2: calcium channel, voltage-dependent, beta 2 subunitCalb1: calbindin 1, 28 kDaCalb2: calbindin 2Cald1: caldesmon 1calm2: calmodulin 2 (phosphorylase kinase, delta)Calr: calreticulinCamk2g: calcium/calmodulin-dependent protein kinase II gammaCamkk1: calcium/calmodulin-dependent protein kinase kinase 1, alphaCamkv: CaM kinase-like vesicle-associatedCanx: calnexinCap1: CAP, adenylate cyclase-associated protein 1 (yeast)Capn1: calpain 1, (mu/l) large subunitCapn5: calpain 5Capn6: calpain 6Capzb: capping protein (actin filament) muscle Z-line, betaCard9: caspase recruitment domain family, member 9Carhsp1: calcium regulated heat stable protein 1, 24 kDaCaskin1: CASK interacting protein 1Casp7: caspase 7, apoptosis-related cysteine peptidaseCast: calpastatinCbp: opsin 1 (cone pigments), long-wave-sensitiveCbx3: chromobox homolog 3 (HP1 gamma homolog, Drosophila)Ccnd2: cyclin D2Ccs: copper chaperone for superoxide dismutaseCct2: chaperonin containing TCP1, subunit 2 (beta)Cd2ap: CD2-associated proteinCd36: CD36 molecule (thrombospondin receptor)Cd86: CD86 moleculeCdc25b: cell division cycle 25 homolog B (S. pombe)Cdc42: cell division cycle 42 (GTP binding protein, 25 kDa)Cdc5l: CDC5 cell division cycle 5-like (S. pombe)Cdh1: cadherin 1, type 1, E-cadherin (epithelial)Cdh10: cadherin 10, type 2 (T2-cadherin)Cdh13: cadherin 13, H-cadherin (heart)Cdh2: cadherin 2, type 1, N-cadherin (neuronal)Cdk5rap2: CDK5 regulatory subunit associated protein 2Cdkn1b: cyclin-dependent kinase inhibitor 1B (p27, Kip1)Cds1: CDP-diacylglycerol synthase (phosphatidate cytidylyltransferase) 1Cdv1: intraflagellar transport 81 homolog (Chlamydomonas)Cebp: CCAAT/enhancer binding protein (C/EBP), alphaCend1: cell cycle exit and neuronal differentiation 1Cenpc1: centromere protein C 1Cenpi: centromere protein ICenta1: ArfGAP with dual PH domains 1Ces1: carboxylesterase 1 (monocyte/macrophage serine esterase 1)Cetn2: centrin, EF-hand protein, 2Cfd: complement factor D (adipsin)Cfl1: cofilin 1 (nonmuscle)Cftr: cystic fibrosis transmembrane conductance regulator (ATP-binding cassette sub-family C, member 7)Chgb: chromogranin B (secretogranin 1)Chka: choline kinase alphaChm: choroideremia (Rab escort protein 1)Chst10: carbohydrate sulfotransferase 10Chx10: visual system homeobox 2Cktsf1b1: gremlin 1, cysteine knot superfamily, homolog (Xenopus laevis)Clcf1: cardiotrophin-like cytokine factor 1Cldn18: claudin 18Clic4: chloride intracellular channel 4Clip3: CAP-GLY domain containing linker protein 3Clta: clathrin, light chain (Lca)Cltb: clathrin, light chain (Lcb)Cltc: clathrin, heavy chain (Hc)Clu: clusterinCnga1: cyclic nucleotide gated channel alpha 1Cngb1: cyclic nucleotide gated channel beta 1Cnot4: CCR4-NOT transcription complex, subunit 4Cnr1: cannabinoid receptor 1 (brain)Col5a3: collagen, type V, alpha 3Copb1: coatomer protein complex, subunit beta 1Cops4: COP9 constitutive photomorphogenic homolog subunit 4 (Arabidopsis)Coro1a: coronin, actin binding protein, 1ACp: ceruloplasmin (ferroxidase)Cpa2: carboxypeptidase A2 (pancreatic)Cpt2: carnitine palmitoyltransferase 2Creb1: cAMP responsive element binding protein 1Crhbp: corticotropin releasing hormone binding proteinCrip2: cysteine-rich protein 2Cript: cysteine-rich PDZ-binding proteinCrmp1: collapsin response mediator protein 1Cry2: cryptochrome 2 (photolyase-like)Csf1: colony stimulating factor 1 (macrophage)Csh1: chorionic somatomammotropin hormone 1 (placental lactogen)Csnk1e: casein kinase 1, epsilonCsnk1g1: casein kinase 1, gamma 1Csnk1g3: casein kinase 1, gamma 3Cspg6: structural maintenance of chromosomes 3Cst6: cystatin E/MCstb: cystatin B (stefin B)Ctnnb1: catenin (cadherin-associated protein), beta 1, 88 kDaCttn: cortactinCugbp2: CUG triplet repeat, RNA binding protein 2Cul5: cullin 5Cutl1: cut-like homeobox 1Cxadr: coxsackie virus and adenovirus receptorCxcl10: chemokine (C-X-C motif) ligand 10Cyb5r4: cytochrome b5 reductase 4Cyln2: CAP-GLY domain containing linker protein 2Cyp19a1: cytochrome P450, family 19, subfamily A, polypeptide 1Cyp1a1: cytochrome P450, family 1, subfamily A, polypeptide 1Cyp4x1: cytochrome P450, family 4, subfamily X, polypeptide 1Dab2ip: DAB2 interacting proteinDbn1: drebrin 1Dctn1: dynactin 1 (p150, glued homolog, Drosophila)Dctn2: dynactin 2 (p50)Dctn4: dynactin 4 (p62)Dcxr: dicarbonyl/L-xylulose reductaseDdah2: dimethylarginine dimethylaminohydrolase 2Ddb1: damage-specific DNA binding protein 1, 127 kDaDdt: D-dopachrome tautomeraseDdx1: DEAD (Asp-Glu-Ala-Asp) box polypeptide 1Ddx19: DEAD (Asp-Glu-Ala-As) box polypeptide 19BDdx27: DEAD (Asp-Glu-Ala-Asp) box polypeptide 27Ddx5: DEAD (Asp-Glu-Ala-Asp) box polypeptide 5Dedd: death effector domain containingDegs1: degenerative spermatocyte homolog 1, lipid desaturase (Drosophila)Des: desminDgkg: diacylglycerol kinase, gamma 90 kDaDhcr7: 7-dehydrocholesterol reductaseDhodh: dihydroorotate dehydrogenaseDhx40: DEAH (Asp-Glu-Ala-His) box polypeptide 40Dia1: cytochrome b5 reductase 3Disc1: disrupted in schizophrenia 1Dkc1: dyskeratosis congenita 1, dyskerinDlat: dihydrolipoamide S-acetyltransferaseDlc1: deleted in liver cancer 1Dlgap2: discs, large (Drosophila) homolog-associated protein 2Dlgap4: discs, large (Drosophila) homolog-associated protein 4Dll1: delta-like 1 (Drosophila)Dnah7: dynein, axonemal, heavy chain 7Dnah9: dynein, axonemal, heavy chain 9Dnajc5: DnaJ (Hsp40) homolog, subfamily C, member 5Dnch1: dynein, cytoplasmic 1, heavy chain 1Dnch2: dynein, cytoplasmic 2, heavy chain 1Dnm1: dynamin 1Dnmt1: DNA (cytosine-5-)-methyltransferase 1Dnmt3a: DNA (cytosine-5-)-methyltransferase 3 alphaDntt: deoxynucleotidyltransferase, terminalDpp3: dipeptidyl-peptidase 3Dpp6: dipeptidyl-peptidase 6Dpyd: dihydropyrimidine dehydrogenaseDrd1ip: calcyon neuron-specific vesicular proteinDrg1: developmentally regulated GTP binding protein 1Dtnb: dystrobrevin, betaDtnbp1: dystrobrevin binding protein 1Duox1: dual oxidase 1Dvl1: dishevelled, dsh homolog 1 (Drosophila)Dyx1c1: dyslexia susceptibility 1 candidate 1Eaf2: ELL associated factor 2Echs1: enoyl Coenzyme A hydratase, short chain, 1, mitochondrialEef1g: eukaryotic translation elongation factor 1 gammaEef2: eukaryotic translation elongation factor 2Eef2k: eukaryotic elongation factor-2 kinaseEfemp2: EGF-containing fibulin-like extracellular matrix protein 2Egfr: epidermal growth factor receptor (erythroblastic leukemia viral (v-erb-b) oncogene homolog, avian)Eif2ak3: eukaryotic translation initiation factor 2-alpha kinase 3Eif2b1: eukaryotic translation initiation factor 2B, subunit 1 alpha, 26 kDaEif2c2: eukaryotic translation initiation factor 2C, 2Eif2s2: eukaryotic translation initiation factor 2, subunit 2 beta, 38 kDaeif4a1: eukaryotic translation initiation factor 4A, isoform 1Elavl3: ELAV (embryonic lethal, abnormal vision, Drosophila)-like 3 (Hu antigen C)ELK1: ELK1, member of ETS oncogene familyEmd: emerinEno2: enolase 2 (gamma, neuronal)Enpp2: ectonucleotide pyrophosphatase/phosphodiesterase 2Entpd8: ectonucleoside triphosphate diphosphohydrolase 8Ephx2: epoxide hydrolase 2, cytoplasmicEpn1: epsin 1Erp29: endoplasmic reticulum protein 29Esd: esterase D/formylglutathione hydrolaseEspn: espinEsrrb: estrogen-related receptor betaEtfa: electron-transfer-flavoprotein, alpha polypeptideEtfb: electron-transfer-flavoprotein, beta polypeptideExoc7: exocyst complex component 7Ezr: ezrinF5: coagulation factor V (proaccelerin, labile factor)Fabp1: fatty acid binding protein 1, liverFancd2: Fanconi anemia, complementation group D2Fat: FAT tumor suppressor homolog 1 (Drosophila)Fat2: FAT tumor suppressor homolog 2 (Drosophila)Fat3: FAT tumor suppressor homolog 3 (Drosophila)Fbn1: fibrillin 1Fdps: farnesyl diphosphate synthaseFgfr1op2: FGFR1 oncogene partner 2Filip1: filamin A interacting protein 1Fkbp1b: FK506 binding protein 1B, 12.6 kDaFlg: filaggrinFlot1: flotillin 1Flot2: flotillin 2Fosl1: FOS-like antigen 1Fosl2: FOS-like antigen 2Fpgt: fucose-1-phosphate guanylyltransferaseFrap1: mechanistic target of rapamycin (serine/threonine kinase)Freq: frequenin homolog (Drosophila)Fyn: FYN oncogene related to SRC, FGR, YESGaa: glucosidase, alpha; acidGabbr1: gamma-aminobutyric acid (GABA) B receptor, 1Gabra3: gamma-aminobutyric acid (GABA) A receptor, alpha 3Gabre: gamma-aminobutyric acid (GABA) A receptor, epsilonGadd45a: growth arrest and DNA-damage-inducible, alphaGalc: galactosylceramidaseGalk1: galactokinase 1Galnt10: UDP-N-acetyl-alpha-D-galactosamine: polypeptide N-acetylgalactosaminyltransferase 10Gars: glycyl-tRNA synthetaseGas7: growth arrest-specific 7Gc: group-specific component (vitamin D binding protein)Gdi1: GDP dissociation inhibitor 1Gdi2: GDP dissociation inhibitor 2Gfap: glial fibrillary acidic proteinGif: gastric intrinsic factor (vitamin B synthesis)Gjb2: gap junction protein, beta 2, 26 kDaGla: galactosidase, alphaGldc: glycine dehydrogenase (decarboxylating)Glra2: glycine receptor, alpha 2Glut3: solute carrier family 2 (facilitated glucose transporter), member 3Gmcl1: germ cell-less homolog 1 (Drosophila)Gmfb: glia maturation factor, betaGna11: guanine nucleotide binding protein (G protein), alpha 11 (Gq class)Gnai1: guanine nucleotide binding protein (G protein), alpha inhibiting activity polypeptide 1Gnai2: guanine nucleotide binding protein (G protein), alpha inhibiting activity polypeptide 2Gnao1: guanine nucleotide binding protein (G protein), alpha activating activity polypeptide OGnaq: guanine nucleotide binding protein (G protein), q polypeptideGnaz: guanine nucleotide binding protein (G protein), alpha z polypeptideGnb2l1: guanine nucleotide binding protein (G protein), beta polypeptide 2-like 1Gnl3: guanine nucleotide binding protein-like 3 (nucleolar)Gnpat: glyceronephosphate O-acyltransferaseGpi: glucose phosphate isomeraseGpm6a: glycoprotein M6AGpr1: G protein-coupled receptor 1Gpr141: G protein-coupled receptor 141Gpr56: G protein-coupled receptor 56Gpsm1: G-protein signaling modulator 1 (AGS3-like, C. elegans)Gpt2: glutamic pyruvate transaminase (alanine aminotransferase) 2Grin1: glutamate receptor, ionotropic, N-methyl D-aspartate 1Grpel1: GrpE-like 1, mitochondrial (E. coli)Gstm2: glutathione S-transferase mu 2 (muscle)Gstm3: glutathione S-transferase mu 3 (brain)Gucy2d: guanylate cyclase 2D, membrane (retina-specific)Gucy2f: guanylate cyclase 2F, retinalH1f0: H1 histone family, member 0H1f4: histone cluster 1, H1eH2afy: H2A histone family, member YHaao: 3-hydroxyanthranilate 3,4-dioxygenaseHap1: huntingtin-associated protein 1Hapln3: hyaluronan and proteoglycan link protein 3Hbld2: iron-sulfur cluster assembly 1 homolog (S. cerevisiae)Hck: hemopoietic cell kinaseHcn1: hyperpolarization activated cyclic nucleotide-gated potassium channel 1Hdac6: histone deacetylase 6Hdgf: hepatoma-derived growth factor (high-mobility group protein 1-like)Hdlbp: high density lipoprotein binding proteinHey1: hairy/enhancer-of-split related with YRPW motif 1Hgf: hepatocyte growth factor (hepapoietin A; scatter factor)Hip1r: huntingtin interacting protein 1 relatedHivep1: human immunodeficiency virus type I enhancer binding protein 1Hk1: hexokinase 1Hmga2: high mobility group AT-hook 2Hmgcr: 3-hydroxy-3-methylglutaryl-Coenzyme A reductaseHmgcs1: 3-hydroxy-3-methylglutaryl-Coenzyme A synthase 1 (soluble)Hmgn3: high mobility group nucleosomal binding domain 3Hn1: hematological and neurological expressed 1Hnf4a: hepatocyte nuclear factor 4, alphaHnmt: histamine N-methyltransferaseHnrnph1: heterogeneous nuclear ribonucleoprotein H1 (H)Hnrpa1: heterogeneous nuclear ribonucleoprotein A1Hnrpk: heterogeneous nuclear ribonucleoprotein KHnrpu: heterogeneous nuclear ribonucleoprotein U (scaffold attachment factor A)hook3: hook homolog 3 (Drosophila)Hps5: Hermansky-Pudlak syndrome 5Hpse: heparanaseHras1: v-Ha-ras Harvey rat sarcoma viral oncogene homologHsd11b2: hydroxysteroid (11-beta) dehydrogenase 2Hsd17B1: hydroxysteroid (17-beta) dehydrogenase 1Hsf1: heat shock transcription factor 1Hsp90ab1: heat shock protein 90 kDa alpha (cytosolic), class B member 1Hspa14: heat shock 70 kDa protein 14Hspe1: heat shock 10 kDa protein 1 (chaperonin 10)Htr2c: 5-hydroxytryptamine (serotonin) receptor 2CHtr3a: 5-hydroxytryptamine (serotonin) receptor 3AHtr4: 5-hydroxytryptamine (serotonin) receptor 4Hyou1: hypoxia up-regulated 1Id2: inhibitor of DNA binding 2, dominant negative helix-loop-helix proteinIdh1: isocitrate dehydrogenase 1 (NADP+), solubleIgf1r: insulin-like growth factor 1 receptorIgf2r: insulin-like growth factor 2 receptorIkbkap: inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase complex-associated proteinIL1b: interleukin 1, betaIl1r2: interleukin 1 receptor, type IIIl1rapl1: interleukin 1 receptor accessory protein-like 1Il6: interleukin 6 (interferon, beta 2)Ilf3: interleukin enhancer binding factor 3, 90 kDaInhbc: inhibin, beta CInpp4a: inositol polyphosphate-4-phosphatase, type I, 107 kDaInpp4b: inositol polyphosphate-4-phosphatase, type II, 105 kDaInpp5d: inositol polyphosphate-5-phosphatase, 145 kDaIrs1: insulin receptor substrate 1Irs2: insulin receptor substrate 2Isg20: interferon stimulated exonuclease gene 20 kDaItga6: integrin, alpha 6Itm2c: integral membrane protein 2CItpr2: inositol 1,4,5-triphosphate receptor, type 2Itpr3: inositol 1,4,5-triphosphate receptor, type 3Ivl: involucrinJag1: jagged 1 (Alagille syndrome)Jak1: Janus kinase 1Jak2: Janus kinase 2Junb: jun B proto-oncogeneKalrn: kalirin, RhoGEF kinaseKatna1: katanin p60 (ATPase-containing) subunit A 1Kcnh1: potassium voltage-gated channel, subfamily H (eag-related), member 1Kcnh2: potassium voltage-gated channel, subfamily H (eag-related), member 2Kcnk2: potassium channel, subfamily K, member 2Kcns1: potassium voltage-gated channel, delayed-rectifier, subfamily S, member 1Kcns3: potassium voltage-gated channel, delayed-rectifier, subfamily S, member 3Kcnt1: potassium channel, subfamily T, member 1Kif5a: kinesin family member 5AKlc1: kinesin light chain 1Klhl12: kelch-like 12 (Drosophila)Kpnb1: karyopherin (importin) beta 1Kras: v-Ki-ras2 Kirsten rat sarcoma viral oncogene homologLama5: laminin, alpha 5Lancl1: LanC lantibiotic synthetase component C-like 1 (bacterial)Lars: leucyl-tRNA synthetaseLbp: lipopolysaccharide binding proteinLcmt1: leucine carboxyl methyltransferase 1Letm1: leucine zipper-EF-hand containing transmembrane protein 1Lgi1: leucine-rich, glioma inactivated 1Lgr7: relaxin/insulin-like family peptide receptor 1Lhfpl4: lipoma HMGIC fusion partner-like 4Lhx3: LIM homeobox 3Lifr: leukemia inhibitory factor receptor alphaLin10: chromosome 16 open reading frame 70LMO7: LIM domain 7Lphn1: latrophilin 1Lphn2: latrophilin 2Lpin1: lipin 1Lrpap1: low density lipoprotein receptor-related protein associated protein 1Lsamp: limbic system-associated membrane proteinLtbp1: latent transforming growth factor beta binding protein 1Luzp1: leucine zipper protein 1Ly6g5b: lymphocyte antigen 6 complex, locus G5BLyar: Ly1 antibody reactive homolog (mouse)LYL1: lymphoblastic leukemia derived sequence 1Lyst: lysosomal trafficking regulatorLzic: leucine zipper and CTNNBIP1 domain containingM6pr: mannose-6-phosphate receptor (cation dependent)Magi3: membrane associated guanylate kinase, WW and PDZ domain containing 3Maoa: monoamine oxidase AMap1lc3a: microtubule-associated protein 1 light chain 3 alphaMap2: microtubule-associated protein 2Map3k7ip2: mitogen-activated protein kinase kinase kinase 7 interacting protein 2Map4: microtubule-associated protein 4Mapk1: mitogen-activated protein kinase 1Mapkapk2: mitogen-activated protein kinase-activated protein kinase 2Mark1: MAP/microtubule affinity-regulating kinase 1Mark3: MAP/microtubule affinity-regulating kinase 3Matr3: matrin 3Mcm7: minichromosome maintenance complex component 7Mdga2: MAM domain containing glycosylphosphatidylinositol anchor 2Mdh1: malate dehydrogenase 1, NAD (soluble)Mecp2: methyl CpG binding protein 2 (Rett syndrome)Mfap3: microfibrillar-associated protein 3Mgat1: mannosyl (alpha-1,3-)-glycoprotein beta-1,2-N-acetylglucosaminyltransferaseMgat5: mannosyl (alpha-1,6-)-glycoprotein beta-1,6-N-acetyl-glucosaminyltransferaseMid1: midline 1 (Opitz/BBB syndrome)Mkln1: muskelin 1, intracellular mediator containing kelch motifsMkrn2: makorin ring finger protein 2Mlp: MARCKS-like 1Mmp10: matrix metallopeptidase 10 (stromelysin 2)Mnat1: ménage à trois homolog 1, cyclin H assembly factor (Xenopus laevis)Mpdz: multiple PDZ domain proteinMpi: mannose phosphate isomeraseMpo: myeloperoxidasempp7: membrane protein, palmitoylated 7 (MAGUK p55 subfamily member 7)mre11: MRE11 meiotic recombination 11 homolog A (S. cerevisiae)Mrpl38: mitochondrial ribosomal protein L38Mrpl9: mitochondrial ribosomal protein L9Mrps9: mitochondrial ribosomal protein S9Msn: moesinMtap: methylthioadenosine phosphorylaseMtdh: metadherinMtmr3: myotubularin-related protein 3Mtr: 5-methyltetrahydrofolate-homocysteine methyltransferaseMtus1: microtubule-associated tumor suppressor 1Mx1: myxovirus (influenza virus) resistance 1, interferon-inducible protein p78 (mouse)Mybpc1: myosin binding protein C, slow typemyc: v-myc myelocytomatosis viral oncogene homolog (avian)Mycbpap: MYCBP associated proteinMyh10: myosin, heavy chain 10, nonmuscleMyh6: myosin, heavy chain 6, cardiac muscle, alphaMyh9: myosin, heavy chain 9, nonmuscleMyo1a: myosin IAMyo1e: myosin IEMyo5a: myosin VA (heavy chain 12, myoxin)Myo5b: myosin VBMyo7a: myosin VIIAMyo9a: myosin IXAMyom1: myomesin 1, 185 kDaNab1: NGFI-A binding protein 1 (EGR1 binding protein 1)Nab2: NGFI-A binding protein 2 (EGR1 binding protein 2)Naca: nascent polypeptide-associated complex alpha subunitNaglu: N-acetylglucosaminidase, alpha-Nap1l3: nucleosome assembly protein 1-like 3Napepld: N-acyl phosphatidylethanolamine phospholipase DNasp: nuclear autoantigenic sperm protein (histone-binding)Ncam1: neural cell adhesion molecule 1Ncam2: neural cell adhesion molecule 2Ncdn: neurochondrinNcl: nucleolinNcstn: nicastrinNdel1: nudE nuclear distribution gene E homolog (A. nidulans)-like 1Ndufa9: NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 9, 39 kDaNdufc2: NADH dehydrogenase (ubiquinone) 1, subcomplex unknown, 2, 14.5 kDaNdufs1: NADH dehydrogenase (ubiquinone) Fe-S protein 1, 75 kDa (NADH-coenzyme Q reductase)Ndufs6: NADH dehydrogenase (ubiquinone) Fe-S protein 6, 13 kDa (NADH-coenzyme Q reductase)Ndufs7: NADH dehydrogenase (ubiquinone) Fe-S protein 7, 20 kDa (NADH-coenzyme Q reductase)Nedd4: neural precursor cell expressed, developmentally down-regulated 4Nef3: neurofilament, medium polypeptideNefh: neurofilament, heavy polypeptideNegr1: neuronal growth regulator 1Nell1: NEL-like 1 (chicken)Neo1: neogenin homolog 1 (chicken)Nes: nestinNexn: nexilin (F actin binding protein)Nf2: neurofibromin 2 (merlin)Nfix: nuclear factor I/X (CCAAT-binding transcription factor)Nfkb1: nuclear factor of kappa light polypeptide gene enhancer in B-cells 1Ninj1: ninjurin 1Nlgn2: neuroligin 2Nlgn3: neuroligin 3Nme2: non-metastatic cells 2, protein (NM23B) expressed inNolc1: nucleolar and coiled-body phosphoprotein 1Nos1: nitric oxide synthase 1 (neuronal)Nos3: nitric oxide synthase 3 (endothelial cell)Notch1: Notch homolog 1, translocation-associated (Drosophila)Notch2: Notch homolog 2 (Drosophila)Notch4: Notch homolog 4 (Drosophila)Npc2: Niemann-Pick disease, type C2Npdc1: neural proliferation, differentiation and control, 1Npepps: aminopeptidase puromycin sensitiveNpm1: nucleophosmin (nucleolar phosphoprotein B23, numatrin)Npr2: natriuretic peptide receptor B/guanylate cyclase B (atrionatriuretic peptide receptor B)Npvf: neuropeptide VF precursorNpy5r: neuropeptide Y receptor Y5Nr1i2: nuclear receptor subfamily 1, group I, member 2Nr5a2: nuclear receptor subfamily 5, group A, member 2Nr6a1: nuclear receptor subfamily 6, group A, member 1Nras: neuroblastoma RAS viral (v-ras) oncogene homologNrbf2: nuclear receptor binding factor 2Nrp2: neuropilin 2Nsf: N-ethylmaleimide-sensitive factorNtrk2: neurotrophic tyrosine kinase, receptor, type 2Nucb1: nucleobindin 1Nucb2: nucleobindin 2Nudc: nuclear distribution gene C homolog (A. nidulans)Nup88: nucleoporin 88 kDaOas3: 2^'-5^'-oligoadenylate synthetase 3, 100 kDaObscn: obscurin, cytoskeletal calmodulin and titin-interacting RhoGEFOciad1: OCIA domain containing 1Odc1: ornithine decarboxylase 1Odf2: outer dense fiber of sperm tails 2Ogfr: opioid growth factor receptorOlfm2: olfactomedin 2Olfm3: olfactomedin 3Omg: oligodendrocyte myelin glycoproteinOptn: optineurinOsbp: oxysterol binding proteinOxr1: oxidation resistance 1P4hb: prolyl 4-hydroxylase, beta polypeptidePabpc1: poly(A) binding protein, cytoplasmic 1Pabpc4: poly(A) binding protein, cytoplasmic 4 (inducible form)Padi2: peptidyl arginine deiminase, type IIPak3: p21 protein (Cdc42/Rac)-activated kinase 3Palm: paralemminPanx1: pannexin 1Pard3: par-3 partitioning defective 3 homolog (C. elegans)Parg: poly (ADP-ribose) glycohydrolasePark7: Parkinson disease (autosomal recessive, early onset) 7Pbp: phosphatidylethanolamine binding protein 1Pcca: propionyl Coenzyme A carboxylase, alpha polypeptidePcdh21: protocadherin 21Pcdha3: protocadherin alpha 3Pcdhb1: protocadherin beta 1Pcdhb10: protocadherin beta 10Pcdhga12: protocadherin gamma subfamily A, 12Pclo: piccolo (presynaptic cytomatrix protein)Pcolce: procollagen C-endopeptidase enhancerPcsk1n: proprotein convertase subtilisin/kexin type 1 inhibitorPcsk5: proprotein convertase subtilisin/kexin type 5Pcyox1: prenylcysteine oxidase 1Pdap1: PDGFA associated protein 1Pdcd4: programmed cell death 4 (neoplastic transformation inhibitor)Pdcl: phosducin-likePde10a: phosphodiesterase 10APde4b: phosphodiesterase 4B, cAMP-specific (phosphodiesterase E4 dunce homolog, Drosophila)Pdlim7: PDZ and LIM domain 7 (enigma)Pea15: phosphoprotein enriched in astrocytes 15Pecr: peroxisomal trans-2-enoyl-CoA reductasePer1: period homolog 1 (Drosophila)Per3: period homolog 3 (Drosophila)Pfkl: phosphofructokinase, liverPGAP1: post-GPI attachment to proteins 1Phactr3: phosphatase and actin regulator 3Phb: prohibitinPhka1: phosphorylase kinase, alpha 1 (muscle)Phkg2: phosphorylase kinase, gamma 2 (testis)Pi4ka: phosphatidylinositol 4-kinase, catalytic, alphaPicalm: phosphatidylinositol binding clathrin assembly proteinPik3c3: phosphoinositide-3-kinase, class 3Pik3cb: phosphoinositide-3-kinase, catalytic, beta polypeptidePik3r2: phosphoinositide-3-kinase, regulatory subunit 2 (beta)Pim1: pim-1 oncogenePip5k2a: phosphatidylinositol-5-phosphate 4-kinase, type II, alphaPitpnm1: phosphatidylinositol transfer protein, membrane-associated 1Pkia: protein kinase (cAMP-dependent, catalytic) inhibitor alphaPkm2: pyruvate kinase, musclePla2g2a: phospholipase A2, group IIA (platelets, synovial fluid)Plb1: phospholipase B1Plcb4: phospholipase C, beta 4Plcd4: phospholipase C, delta 4Plec1: plectin 1, intermediate filament binding protein 500kDaPlk1: polo-like kinase 1 (Drosophila)Pnkp: polynucleotide kinase 3'-phosphatasePnma1: paraneoplastic antigen MA1Ppara: peroxisome proliferator-activated receptor alphaPpargc1b: peroxisome proliferator-activated receptor gamma, coactivator 1 betappfibp2: PTPRF interacting protein, binding protein 2 (liprin beta 2)Ppia: peptidylprolyl isomerase A (cyclophilin A)Ppm2c: pyruvate dehydrogenase phosphatase catalytic subunit 1Ppp1r14b: protein phosphatase 1, regulatory (inhibitor) subunit 14BPpp1r1a: protein phosphatase 1, regulatory (inhibitor) subunit 1APpp1r9a: protein phosphatase 1, regulatory (inhibitor) subunit 9APpp2r1a: protein phosphatase 2 (formerly 2A), regulatory subunit A, alpha isoformPpp3cc: protein phosphatase 3 (formerly 2B), catalytic subunit, gamma isoformPqlc1: PQ loop repeat containing 1Prdx1: peroxiredoxin 1Prdx6: peroxiredoxin 6Prg3: proteoglycan 3Prkaa2: protein kinase, AMP-activated, alpha 2 catalytic subunitPrkaca: protein kinase, cAMP-dependent, catalytic, alphaPrkar1a: protein kinase, cAMP-dependent, regulatory, type I, alpha (tissue specific extinguisher 1)Prkar2a: protein kinase, cAMP-dependent, regulatory, type II, alphaPrkcd: protein kinase C, deltaPRKCQ: protein kinase C, thetaPrkwnk1: WNK lysine deficient protein kinase 1Prlh: prolactin releasing hormonePrmt3: protein arginine methyltransferase 3Prpsap2: phosphoribosyl pyrophosphate synthetase-associated protein 2Prrx2: paired related homeobox 2Prss12: protease, serine, 12 (neurotrypsin, motopsin)Prss15: lon peptidase 1, mitochondrialPrx: periaxinPsap: prosaposinPscd2: cytohesin 2Pscd3: cytohesin 3Psg4: pregnancy specific beta-1-glycoprotein 4Psma1: proteasome (prosome, macropain) subunit, alpha type, 1Psma2: proteasome (prosome, macropain) subunit, alpha type, 2Psmc4: proteasome (prosome, macropain) 26S subunit, ATPase, 4Psme2: proteasome (prosome, macropain) activator subunit 2 (PA28 beta)Ptbp1: polypyrimidine tract binding protein 1Ptch1: patched homolog 1 (Drosophila)Pth: parathyroid hormonePthr2: parathyroid hormone 2 receptorPtk2b: PTK2B protein tyrosine kinase 2 betaPtp4a1: protein tyrosine phosphatase type IVA, member 1Ptpn11: protein tyrosine phosphatase, non-receptor type 11Ptpn23: protein tyrosine phosphatase, non-receptor type 23Ptprj: protein tyrosine phosphatase, receptor type, JPtprr: protein tyrosine phosphatase, receptor type, RPtprv: protein tyrosine phosphatase, receptor type, V (pseudogene)Pxn: paxillinPygl: phosphorylase, glycogen, liverQscn6: quiescin Q6 sulfhydryl oxidase 1Rab10: RAB10, member RAS oncogene familyRab14: RAB14, member RAS oncogene familyRab2: RAB2A, member RAS oncogene familyRab21: RAB21, member RAS oncogene familyRab35: RAB35, member RAS oncogene familyRab3il1: RAB3A interacting protein (rabin3)-like 1Rab4a: RAB4A, member RAS oncogene familyRab5a: RAB5A, member RAS oncogene familyRab7: RAB7A, member RAS oncogene familyRab9: RAB9A, member RAS oncogene familyRabac1: Rab acceptor 1 (prenylated)Rabggta: Rab geranylgeranyltransferase, alpha subunitRac1: ras-related C3 botulinum toxin substrate 1 (rho family, small GTP binding protein Rac1)Rala: v-ral simian leukemia viral oncogene homolog A (ras related)RalB: v-ral simian leukemia viral oncogene homolog B (ras related; GTP binding protein)Ralb: v-ral simian leukemia viral oncogene homolog B (ras related; GTP binding protein)Raly: RNA binding protein, autoantigenic (hnRNP associated with lethal yellow homolog (mouse))RanGap1: Ran GTPase activating protein 1Rap2b: RAP2B, member of RAS oncogene familyRbbp6: retinoblastoma binding protein 6Rbl2: retinoblastoma-like 2 (p130)Rbm3: RNA binding motif (RNP1, RRM) protein 3Rcn1: reticulocalbin 1, EF-hand calcium binding domainRcvrn: recoverinRdh10: retinol dehydrogenase 10 (all-trans)Rdx: radixinRest: RE1-silencing transcription factorRgs4: regulator of G-protein signaling 4Rgs5: regulator of G-protein signaling 5Rgs7: regulator of G-protein signaling 7Rhoa: ras homolog gene family, member ARhoB: ras homolog gene family, member BRhoj: ras homolog gene family, member JRims1: regulating synaptic membrane exocytosis 1Rnasel: ribonuclease L (2^',5^'-oligoisoadenylate synthetase-dependent)Rnf36: tripartite motif-containing 69Rnf40: ring finger protein 40Robo1: roundabout, axon guidance receptor, homolog 1 (Drosophila)Robo4: roundabout homolog 4, magic roundabout (Drosophila)Rock1: Rho-associated, coiled-coil containing protein kinase 1Rock2: Rho-associated, coiled-coil containing protein kinase 2rora: RAR-related orphan receptor ARpe65: retinal pigment epithelium-specific protein 65 kDaRpl13: ribosomal protein L13Rpl6: ribosomal protein L6Rplp1: ribosomal protein, large, P1Rpn2: ribophorin IIRps15: ribosomal protein S15Rps16: ribosomal protein S16Rps6ka2: ribosomal protein S6 kinase, 90 kDa, polypeptide 2Rtcd1: RNA terminal phosphate cyclase domain 1Rtkn: rhotekinRtn1: reticulon 1Rtn3: reticulon 3Rtn4: reticulon 4Rtn4r: reticulon 4 receptorSamsn1: SAM domain, SH3 domain and nuclear localization signals 1Sardh: sarcosine dehydrogenaseSart1: squamous cell carcinoma antigen recognized by T cellsSbds: Shwachman-Bodian-Diamond syndromeSc4mol: sterol-C4-methyl oxidase-likeSca10: ataxin 10Scg2: secretogranin II (chromogranin C)Scg3: secretogranin IIIScn1a: sodium channel, voltage-gated, type I, alpha subunitScn2a1: sodium channel, voltage-gated, type II, alpha subunitScn5a: sodium channel, voltage-gated, type V, alpha subunitScn8a: sodium channel, voltage gated, type VIII, alpha subunitScoc: short coiled-coil proteinScp2: sterol carrier protein 2SCYB11: chemokine (C-X-C motif) ligand 11Scye1: aminoacyl tRNA synthetase complex-interacting multifunctional protein 1Sdfr1: neuroplastinSdpr: serum deprivation responseSH3gl1: SH3-domain GRB2-like 1SH3glb1: SH3-domain GRB2-like endophilin B1Shank1: SH3 and multiple ankyrin repeat domains 1Sirpa: signal-regulatory protein alphaSkiv2l2: superkiller viralicidic activity 2-like 2 (S. cerevisiae)Slc12a2: solute carrier family 12 (sodium/potassium/chloride transporters), member 2Slc12a9: solute carrier family 12 (potassium/chloride transporters), member 9Slc13a3: solute carrier family 13 (sodium-dependent dicarboxylate transporter), member 3Slc17a6: solute carrier family 17 (sodium-dependent inorganic phosphate cotransporter), member 6Slc1a1: solute carrier family 1 (neuronal/epithelial high affinity glutamate transporter, system Xag), member 1Slc26a4: solute carrier family 26, member 4Slc27a5: solute carrier family 27 (fatty acid transporter), member 5Slc30a1: solute carrier family 30 (zinc transporter), member 1Slc44a4: solute carrier family 44, member 4Slc5a1: solute carrier family 5 (sodium/glucose cotransporter), member 1Slc6a8: solute carrier family 6 (neurotransmitter transporter, creatine), member 8Slc8a1: solute carrier family 8 (sodium/calcium exchanger), member 1Smad4: SMAD family member 4Smc1l1: structural maintenance of chromosomes 1ASmoc1: SPARC related modular calcium binding 1Snai2: snail homolog 2 (Drosophila)Snap25: synaptosomal-associated protein, 25 kDaSnap91: synaptosomal-associated protein, 91 kDa homolog (mouse)Snca: synuclein, alpha (non A4 component of amyloid precursor)Sncb: synuclein, betaSnx3: sorting nexin 3Snx7: sorting nexin 7sod1: superoxide dismutase 1, solubleSod2: superoxide dismutase 2, mitochondrialSon: SON DNA binding proteinSord: sorbitol dehydrogenaseSox5: SRY (sex determining region Y)-box 5Sp4: Sp4 transcription factorSp7: Sp7 transcription factorSqle: squalene epoxidaseSrfbp1: serum response factor binding protein 1Sst: somatostatinSt6gal2: ST6 beta-galactosamide alpha-2,6-sialyltransferase 2St7l: suppression of tumorigenicity 7 likeStard3nl: STARD3 N-terminal likeStat3: signal transducer and activator of transcription 3 (acute-phase response factor)Stat5a: signal transducer and activator of transcription 5AStip1: stress-induced-phosphoprotein 1Stk2: NIMA (never in mitosis gene a)-related kinase 4Stk22a: testis-specific serine kinase 1A pseudogeneStmn1: stathmin 1Stmn2: stathmin-like 2Stmn4: stathmin-like 4Strbp: spermatid perinuclear RNA binding proteinStx1a: syntaxin 1A (brain)Stx1b2: syntaxin 1BStx5: syntaxin 5stxbp1: syntaxin binding protein 1Stxbp3: syntaxin binding protein 3Sulf1: sulfatase 1Svop: SV2 related protein homolog (rat)SYAP1: synapse associated protein 1, SAP47 homolog (Drosophila)Sycp1: synaptonemal complex protein 1Sycp2: synaptonemal complex protein 2Synj2: synaptojanin 2Syt3: synaptotagmin IIISyt4: synaptotagmin IVTacc2: transforming, acidic coiled-coil containing protein 2Tacc3: transforming, acidic coiled-coil containing protein 3Tbx2: T-box 2Tceb3: transcription elongation factor B (SIII), polypeptide 3 (110 kDa, elongin A)Tcp1: t-complex 1Tcp11: t-complex 11 homolog (mouse)Tdg: thymine-DNA glycosylaseTdrd7: tudor domain containing 7Tesk2: testis-specific kinase 2Tfrc: transferrin receptor (p90, CD71)Tgfb1: transforming growth factor, beta 1Thrap3: thyroid hormone receptor associated protein 3Thrb: thyroid hormone receptor, beta (erythroblastic leukemia viral (v-erb-a) oncogene homolog 2, avian)Thy1: Thy-1 cell surface antigenTinag: tubulointerstitial nephritis antigenTkt: transketolaseTle3: transducin-like enhancer of split 3 (E(sp1) homolog, Drosophila)Tlr5: toll-like receptor 5Tm4sf8: tetraspanin 3Tm9sf2: transmembrane 9 superfamily member 2Tmeff1: transmembrane protein with EGF-like and two follistatin-like domains 1Tmem17: transmembrane protein 17Tmlhe: trimethyllysine hydroxylase, epsilonTmod2: tropomodulin 2 (neuronal)Tmpo: thymopoietinTnfrsf14: tumor necrosis factor receptor superfamily, member 14 (herpesvirus entry mediator)Top1: topoisomerase (DNA) ITpd52l2: tumor protein D52-like 2Tpm4: tropomyosin 4Tra1: heat shock protein 90kDa beta (Grp94), member 1Traf4: TNF receptor-associated factor 4Trib3: tribbles homolog 3 (Drosophila)Trim10: tripartite motif-containing 10Trim25: tripartite motif-containing 25Trim50: tripartite motif-containing 50Trpa1: transient receptor potential cation channel, subfamily A, member 1TrpV6: transient receptor potential cation channel, subfamily V, member 6Tsc1: tuberous sclerosis 1Tsga10: testis specific, 10Tshr: thyroid stimulating hormone receptorTtc1: tetratricopeptide repeat domain 1Ttn: titinTub: tubby homolog (mouse)Tubb: tubulin, betaTubb2: tubulin, beta 2ATxn: thioredoxinU2af2: U2 small nuclear RNA auxiliary factor 2Ubc: ubiquitin CUbe2l3: ubiquitin-conjugating enzyme E2L 3Ubqln1: ubiquilin 1Uchl1: ubiquitin carboxyl-terminal esterase L1 (ubiquitin thiolesterase)Ugcgl1: UDP-glucose glycoprotein glucosyltransferase 1Uhrf1: ubiquitin-like with PHD and ring finger domains 1Unc13: unc-13 homolog B (C. elegans)Unc13a: unc-13 homolog A (C. elegans)Unc13d: unc-13 homolog D (C. elegans)Uqcrfs1: ubiquinol-cytochrome c reductase, Rieske iron-sulfur polypeptide 1Usp14: ubiquitin specific peptidase 14 (tRNA-guanine transglycosylase)Usp15: ubiquitin specific peptidase 15Vamp2: vesicle-associated membrane protein 2 (synaptobrevin 2)Vangl2: vang-like 2 (van gogh, Drosophila)Vapa: VAMP (vesicle-associated membrane protein)-associated protein A, 33 kDaVapb: VAMP (vesicle-associated membrane protein)-associated protein B and CVav1: vav 1 guanine nucleotide exchange factorVcp: valosin-containing proteinVdac2: voltage-dependent anion channel 2Vegfa: vascular endothelial growth factor AVgf: VGF nerve growth factor inducibleViaat: solute carrier family 32 (GABA vesicular transporter), member 1Vim: vimentinVldlr: very low density lipoprotein receptorVps4a: vacuolar protein sorting 4 homolog A (S. cerevisiae)Vps52: vacuolar protein sorting 52 homolog (S. cerevisiae)Vps54: vacuolar protein sorting 54 homolog (S. cerevisiae)Vsnl1: visinin-like 1Vti1a: vesicle transport through interaction with t-SNAREs homolog 1A (yeast)Vtn: vitronectinWbp11: WW domain binding protein 11Wbscr1: eukaryotic translation initiation factor 4HWhsc2: Wolf-Hirschhorn syndrome candidate 2Wif1: WNT inhibitory factor 1Wnk4: WNK lysine deficient protein kinase 4Wrnip1: Werner helicase interacting protein 1Xpo7: exportin 7Xrcc5: X-ray repair complementing defective repair in Chinese hamster cells 5Ybx1: Y box binding protein 1yes1: v-yes-1 Yamaguchi sarcoma viral oncogene homolog 1Ywhah: tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, eta polypeptideYwhaq: tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, theta polypeptideZbtb7a: zinc finger and BTB domain containing 7AZeb1: zinc finger E-box binding homeobox 1Zfhx2: zinc finger homeobox 2Zfp57: zinc finger protein 57 homolog (mouse)Zmynd19: zinc finger, MYND-type containing 19Znf219: zinc finger protein 219Znf291: S-phase cyclin A-associated protein in the ERZnf292: zinc finger protein 292Znf382: zinc finger protein 382.

C.

Cellular signaling pathway clusters of extracted proteins from primary cortical tissue. Specific cellular signaling pathway clusters generated in an un-biased manner using Ingenuity Pathway Analysis (v. 8.5). The relative score generated for the degree of pathway population by proteins from the respective input sets (control or 3xTgAD) is shown in bold. The following are different types of signaling pathways.

C.1. ERK/MAPK Signaling (Enrichment Ratio*−log10(𝑝))

Control Protein (1.32502)
PPP2R2A, CRK, PPP1R14B, DUSP2, PTK2, SHC1, PAK1, PPP1R10, PPP1R7, PIK3CG, STAT1, PRKCA, ETS1, SRC, PAK2, YWHAB, CRKL, PRKAR2A, STAT3, PLA2G4C, FOS, PPP2CB, PPP2R1A, PRKAR2B, PRKCI, PAK3, PPP2R2B, PRKACA, PPP2R5E, ELK1, PPP2R1B, PRKAR1A, PRKCB.

3xTgAD Protein (0.1537)
PXN, YWHAH, PTK2B, RAC1, PRKAR2A, PLA2G2A, STAT3, MYC, YWHAQ (includes EG:10971), PPP2R1A, PAK3, PIK3C3, PRKCD, PRKACA, PIK3CB, PIK3R2, ELK1, FYN, PRKAR1A.

C.2. Inositol Phosphate Metabolism (Enrichment Ratio*−log10(𝑝))

Control Protein (0.86424)
PDIA3, OCRL, PAK1, PIK3CG, PRKAA2, PLCB1, PLCL1, PI4KA, PMPCA, ATM, GRK4, PRKCQ, PAK2, CDK7, CDK6, PLK1, GRK5, ITPKA, SYNJ2, PIP5K1A, PAK3, SYNJ1, PIP5K1C, GRK6, PIP4K2A, PIP4K2C, CDK2.

3xTgAD Protein (0.15355)
PLK1, INPP5D, SYNJ2, INPP4A, INPP4B, INPP4B, PAK3, PIM1, PRKCD, PIK3C3, PRKAA2, PIK3CB, PIK3R2, PIP4K2A, PLCD4, PI4KA, ATM.

C.3. Wnt/β-Catenin Signaling (Enrichment Ratio*−log10(𝑝))

Control Protein (0.5609)
PPP2R2A, SOX10, CSNK1E, WIF1, WNT7A, TGFB1, SMO, CSNK2A1, CSNK2B, CTNNB1, SRC, SFRP4, GJA1, CSNK1G2, DVL1, FZD9, PPP2CB, CDH2, CDH1, PPP2R1A, PPP2R2B, TLE3, PPP2R5E, UBC, PPP2R1B, WNT5A.

3xTgAD Protein (0.12772)
CSNK1G1, CSNK1G3, DVL1, ACVR1, APC, MYC, CSNK1E, PPP2R1A, CDH2, CDH1, WIF1, TGFB1, GNAO1, TLE3, UBC, CTNNB1, SOX5 (includes EG:6660).

C.4. Calcium Signaling (Enrichment Ratio*−log10(𝑝))

Control Protein (0.33825)
TRPC2, GRIN2A, TNNI2, GRIA1, RCAN2, CALM2, CHRNB4, TRPC5, TNNT3, RYR3, GRIK1, GRIN2B, PRKAR2A, TRPC4, PPP3CC, TRPC7, CHRNG, PRKAR2B, TPM3, CAMKK1, PRKACA, TNNI1, CHRNB3, CAMKK2, PRKAR1A.

3xTgAD Protein (0.110875)
RAP2B, MYH10, CALR, MYH6, ATP2B1, PRKAR2A, TPM4, PPP3CC, ATP2B2, HDAC6, TRPV6, HTR3A, CAMKK1, PRKACA, MYH9, SLC8A1, ACTA1, PRKAR1A.

C.5. Tight Junction Signaling (Enrichment Ratio*−log10(𝑝))

Control Protein (0.4147)
TJP2, CDC42, TJP1, PPP2R2A, CLDN19, VAPA, PRKAR2A, PRKCZ, FOS, PPP2CB, PPP2R1A, PRKCI, PRKAR2B, CLDN4, CLDN1, TGFB1, PPP2R2B, PRKACA, PPP2R5E, STX4, CTNNB1, PPP2R1B, PRKAR1A.

3xTgAD Protein (0.24514)
MYH10, MYH6, CDC42, ACTB, HSF1, CLDN18, VAPA, RAC1, PRKAR2A, MPDZ, PPP2R1A, TGFB1, RHOA, CEBPA, PRKACA, MYH9, CTNNB1, ACTA1, PRKAR1A.

C.6. NF-κB Signaling (Enrichment Ratio*−log10(𝑝))

Control Protein (0.12096)
PRKCQ, EGF, PRKCZ, TLR9, TLR4, TLR5, PIK3CG, TLR6, PRKACA, CSNK2A1, PDGFRA, TLR3, CSNK2B, PRKCB, EGFR.

3xTgAD Protein (0.0190128)
IL1R2, TLR5, BCL10, PIK3C3, PRKACA, IL1B, PIK3CB, PIK3R2, NFKB1, EGFR.

C.7. PTEN Signaling (Enrichment Ratio*−log10(𝑝))

Control Protein (0.1368)
PTK2, SHC1, CDC42, PIK3CG, CSNK2A1, PDGFRA, CSNK2B, CDKN1B, PRKCZ, FASLG, EGFR.

3xTgAD Protein (0.1199)
CDC42, YWHAH, RAC1, PIK3CB, PIK3R2, CDKN1B, NFKB1, INPP5D, EGFR, MAGI3.

C.8. SAPK/JNK Signaling (Enrichment Ratio*−log10(𝑝))

Control Protein (0.0544984)
SHC1, CDC42, GADD45A, CRKL, PIK3CG, CRK, ELK1, GNG7.

3xTgAD Protein (0.0717288)
CDC42, GADD45A, IRS1, PIK3C3, RAC1, PIK3CB, PIK3R2, ELK1, HNRNPK.

C.9. PI3K/AKT Signaling (Enrichment Ratio*−log10(𝑝))

Control Protein (0.15481)
TSC1, PPP2R2A, YWHAB, PRKCZ, PPP2CB, SHC1, PPP2R1A, PIK3CG, TSC2, PPP2R2B, PPP2R5E, CDKN1B, CTNNB1, PPP2R1B.

3xTgAD Protein (0.19323)
TSC1, JAK1, YWHAH, JAK2, NOS3, INPP5D, YWHAQ (includes EG:10971), MTOR, PPP2R1A, HSP90AB1, PIK3CB, PIK3R2, CDKN1B, CTNNB1.

C.10. p38 MAPK Signaling (Enrichment Ratio*−log10(𝑝))

Control Protein (0)
 

3xTgAD Protein (0.0630702)
IL1R2, MYC, TGFB1, MAP3K7IP2, IL1B, PLA2G2A, EEF2K, MAPKAPK2, ELK1.

C.11. p53 Signaling (Enrichment Ratio*−log10(𝑝))

Control Protein (0.037996)
GADD45A, FASN, PIK3CG, SNAI2, CTNNB1, CDK2, ATM, SERPINE2.

3xTgAD Protein (0.12075)
CCND2, GADD45A, PIK3C3, SNAI2, CABC1, PIK3CB, PIK3R2, BAX, CTNNB1, ATM.

C.12. JAK/Stat Signaling (Enrichment Ratio*−log10(𝑝))

Control Protein (0.051714)
SHC1, SOCS1, PTPN11, PIK3CG, STAT3, STAT1.

3xTgAD Protein (0.25857)
STAT5A, MTOR, JAK1, PTPN11, PIK3C3, PIK3CB, STAT3, PIK3R2, JAK2.

D.

Neuronal function pathway clusters of extracted proteins from primary cortical tissue. Specific neuronal function pathway clusters generated in an un-biased manner using Ingenuity Pathway Analysis (v. 8.5). The relative score generated for the degree of pathway population by proteins from the respective input sets (control or 3xTgAD) is shown in bold. The following are different types of signaling pathways.

D.1. Synaptic Long-Term Potentiation (Enrichment Ratio*−log10(𝑝))

Control Protein (1.27872)
GRIN2B, GRIN2A, PRKCQ, PPP1R1A, GRIA1, PRKAR2A, CALM2, CACNA1C, PPP3CC, GRM4, PPP1R14B, PRKCZ, GRM5, PRKCI, PRKAR2B, PPP1R10, PPP1R7, PPP1R14D, PRKACA, PLCB1, PRKD1, PRKCA, PRKAR1A, PRKCB

3xTgAD Protein (0)
 

D.2. Axonal Guidance Signaling (Enrichment Ratio*−log10(𝑝))

Control Protein (0.69525)
NOS1, GUCY1B2, PRKCQ, GUCY1A3, GUCY2D, PPP2R2A, GRID2, GRIA1, GRM4, PRKCZ, GRM5, PPP2CB, PPP2R1A, PRKCI, PPP2R2B, RYR3, GUCY1A2, PLCB1, PPP2R5E, PPP2R1B, PRKD1, PRKCA, PRKCB.

3xTgAD Protein (0.1918)
NOS1, GUCY2D, GNAI1, PLA2G2A, GNAZ, NOS3, PRDX6, GNAI2, PPP2R1A, PRKCD, GNAO1, IGF1R, GUCY2F, ADCY8, NPR2.

D.3. Synaptic Long-Term Depression (Enrichment Ratio*−log10(𝑝))

Control Protein (0.47428)
NOS1, GUCY1B2, PRKCQ, GUCY1A3, GUCY2D, PPP2R2A, GRID2, GRIA1, GRM4, PRKCZ, GRM5, PPP2CB, PPP2R1A, PRKCI, PPP2R2B, RYR3, GUCY1A2, PLCB1, PPP2R5E, PPP2R1B, PRKD1, PRKCA, PRKCB.

3xTgAD Protein (0.11112)
NOS1, GUCY2D, GNAI1, PLA2G2A, GNAZ, NOS3, PRDX6, GNAI2, PPP2R1A, PRKCD, GNAO1, IGF1R, GUCY2F, ADCY8, NPR2.

D.4. Parkinson's Signaling (Enrichment Ratio*−log10(𝑝))

Control Protein (0.168256)
UCHL1, PARK7, SNCA.

3xTgAD Protein (0.18656)
UCHL1, PARK7, SNCA.

D.5. Huntington's Disease Signaling (Enrichment Ratio*−log10(𝑝))

Control Protein (0.20048)
EGF, GNG7, PRKCZ, TGM2, CTSD, SHC1, PIK3CG, VAMP3, PLCB1, PRKD1, PRKCA, EGFR, SDHA, GRIN2B, PRKCQ, YKT6, SH3GL3, STX1A, SNAP25, TAF9B, GRM5, PRKCI, UBC, GOSR2, SNCA, PRKCB.

3xTgAD Protein (0.36179)
VTI1A, HSPA14, REST, GNB2L1, HDAC6, NSF, MTOR, PIK3C3, IGF1R, PIK3R2, EGFR, CAPN5, CAPN6, CLTC, BAX, STX1A, SNAP25, DNM1, DNAJC5, ATP5B, CAPN1, PRKCD, HAP1, DCTN1, PIK3CB, UBC, SNCA, CASP7.

D.6. Regulation of Actin-Based Motility by Rho (Enrichment Ratio*−log10(𝑝))

Control Protein (0.1476)
PIP5K1A, WIPF1, PAK1, PAK2, CDC42, CFL1, PAK3, PIP5K1C, PIP4K2A, PIP4K2C, PI4KA.

3xTgAD Protein (0.3243)
CDC42, CFL1, ACTB, RAC1, RHOJ, ROCK1, PAK3, RHOB, RHOA, ARHGDIA, PIP4K2A, ACTA1, PI4KA.

D.7. Amyotrophic Lateral Sclerosis Signaling (Enrichment Ratio*−log10(𝑝))

Control Protein (0.23184)
NOS1, GRIN2B, GRIN2A, SOD1, GRIA1, PGF, VEGFA, PAK1, GRIK4, PIK3CG, CAT, GLUL, SSR4.

3xTgAD Protein (0.55955)
NOS1, CAPN5, CAPN6, SOD1, RAB5A, RAC1, NEFH, BAX, CCS, VEGFA, CAPN1, PIK3C3, NEFM, PIK3CB, PIK3R2, CASP7.

D.8. Actin Cytoskeleton Signaling (Enrichment Ratio*−log10(𝑝))

Control Protein (0.0763861)
PAK2, CFL1, CDC42, CRKL, EGF, CRK, TTN, PTK2, SHC1, PAK1, PIP5K1A, PAK3, PIP5K1C, FGF18, PIK3CG, EZR, FGF23, PIP4K2A, PIP4K2C, GIT1.

3xTgAD Protein (0.44928)
MYH10, MYH6, CDC42, ROCK2, PIK3C3, EZR, PIK3R2, LBP, ACTA1, PXN, ARHGEF12, CFL1, ACTB, RAC1, RDX, APC, TTN, ROCK1, PAK3, RHOA, ARHGEF6, MYH9, VAV1, PIK3CB, ACTN4, PIP4K2A, MSN.

D.9. Amyloid Processing (Enrichment Ratio*−log10(𝑝))

Control Protein (0.20636)
CSNK1E, PRKAR2B, CSNK2A, PRKAR2A, PRKACA, NCSTN, CSNK2B, PRKAR1A.

3xTgAD Protein (0.66144)
CSNK1E, CAPN5, CAPN6, CAPN1, MARK1, PRKAR2A, PRKACA, NCSTN, BACE1, APP, PRKAR1A.

E.

Energy regulation/Metabolism pathway clusters of extracted proteins from primary cortical tissue. Specific energy regulation/metabolism pathway clusters generated in an un-biased manner using Ingenuity Pathway Analysis (v. 8.5). The relative score generated for the degree of pathway population by proteins from the respective input sets (control or 3xTgAD) is shown in bold. The following are different types of signaling pathways.

E.1. Amino Sugars Metabolism (Enrichment Ratio*−log10(𝑝))

Control Protein (0.61425)
FMO3, PDE7A, PDE10A, GM2A, CYB5R1, PDE4A, PDE4B, PDE1A, PDE4D, GFPT2, PDE1C, PDE7B, GALK1, CYB5R3.

3xTgAD Protein (0.0471409)
HK1, CYB5R4, PDE10A, GALK1, CYB5R3, PDE4B.

E.2. Pentose Phosphate Pathway (Enrichment Ratio*−log10(𝑝))

Control Protein (0.48608)
GPI, PGD, TKT, TALDO1, PRPSAP1, PGM1, PRPSAP2, PFKP, PFKL, PDHB, PFKM.

3xTgAD Protein (0.0245154)
GPI, TKT, PRPSAP2, PFKL.

E.3. Glutamate Metabolism (Enrichment Ratio*−log10(𝑝))

Control Protein (0.31165)
FMO3, GPT, GLUL, GCLC, GLUD1, GOT1, GOT2, GFPT2, EPRS.

3xTgAD Protein (0)
 

E.4. Pantothenate and CoA Biosynthesis (Enrichment Ratio*−log10(𝑝))

Control Protein (0.34188)
ENPP3, CRMP1, BCAT1, DPYD, DPYSL3, ENPP5, ENPP2.

3xTgAD Protein (0.0348908)
CRMP1, DPYD, ENPP2.

E.5. Glycolysis/Gluconeogenesis (Enrichment Ratio*−log10(𝑝))

Control Protein (0.28363)
PKM2, PGK1, ENO3, ENO2, GAPDH (includes EG:2597), PGM1, ALDH1L1, PFKP, PFKL, PDHB, PFKM, GPI, GALK1, DLAT, PGAM1, DLD.

3xTgAD Protein (0.0610449)
PKM2, HK1, ADH1A, GPI, ALDH1A3, DLAT, GALK1, ENO2, PFKL, ACSL1.

E.6. Citrate Cycle (Enrichment Ratio*−log10(𝑝))

Control Protein (0.1581)
SDHA, PC, CS, SUCLG1, DLD, PCK1.

3xTgAD Protein (0)
 

E.7. Galactose Metabolism

Control Protein (0.104958)
GLA, GALT, GALK1, GAA, PGM1, PFKP, PFKL, PFKM.

3xTgAD Protein (0.0486688)
HK1, GLA, GALK1, GAA, PFKL, AKR1B1.

E.8. Glycosphingolipid Biosynthesis—Globoseries (Enrichment Ratio*−log10(𝑝))

Control Protein (0.0411384)
GLA, ST3GAL1, GM2A.

3xTgAD Protein (0)
 

E.9. Glycosphingolipid Biosynthesis—Ganglioseries (Enrichment Ratio*−log10(𝑝))

Control Protein (0.008832)
ST3GAL1, GM2A.

3xTgAD Protein (0)
 

E.10. N-Glycan Biosynthesis (Enrichment Ratio*−log10(𝑝))

Control Protein (0)
 

3xTgAD Protein (0.015272)
RPN2, ST6GAL2, MGAT5, MGAT1.

E.11. Pentose and Glucuronate Interconversions (Enrichment Ratio*−log10(𝑝))

Control Protein (0)
 

3xTgAD Protein (0.0184464)
UCHL1, B3GAT1, HPSE, DCXR, AKR1B1.

E.12. Fatty Acid Elongation in Mitochondria (Enrichment Ratio*−log10(𝑝))

Control Protein (0)
 

3xTgAD Protein (0.0206016)
ECHS1, PECR.

E.13. Glycerophospholipid Metabolism (Enrichment Ratio*−log10(𝑝))

Control Protein (0.0232106)
GPAM, PCYT1B, PLD3, CDS1, PDIA3, GNPAT, DGKB, DGKG, PLCB1, PLCL1.

3xTgAD Protein (0.048204)
AGPAT4, CDS1, GNPAT, CHKA, AGPAT1, DGKG, PLA2G2A, CLCF1, PHKA1, PLCD4, PRDX6.

E.14. Fatty Acid Biosynthesis (Enrichment Ratio*−log10(𝑝))

Control Protein (0)
 

3xTgAD Protein (0.0329256)
ACACB, ACACA.

E.15. Purine Metabolism (Enrichment Ratio*−log10(𝑝))

Control Protein (0.08616)
ENTPD8, PDE7A, PDE4A, DNTT, PDE1A, PDE4D, PSMC5, PDE7B, VCP, DHX16, ENPP2, PRPSAP2, PKM2, TJP2, GUCY1B2, GUCY1A3, GUCY2D, PDE10A, ENPP5, PDE4B, PDE1C, ENPP3, PSMC1, ENTPD2, PRPSAP1, GUCY1A2, PDE5A, DDX1, GMPR2, PSMC3.

3xTgAD Protein (0.124932)
MYH6, ENTPD8, NME2, DNTT, WRNIP1, ABCC1, VCP, KATNA1, ATP5H (includes EG:10476), ENPP2, PRPSAP2, ADCY8, ATP5F1, ATP5I, ATP5J, PKM2, ATP1B1, GUCY2D, PDE10A, AMPD1, ATP5A1, AK3, PSMC4, PDE4B, DDX19B, ATP5B, GUCY2F, MYH9, DDX1, NPR2.

E.16. Pyruvate Metabolism (Enrichment Ratio*−log10(𝑝))

Control Protein (0.0214935)
PKM2, PC, DLAT, DLD, PCK1, PDHB, GLO1.

3xTgAD Protein (0.070173)
PKM2, ACACB, ALDH1A3, DLAT, ACAT1, ACACA, MDH1, AKR1B1, ACSL1.

E.17. Butanoate Metabolism (Enrichment Ratio*−log10(𝑝))

Control Protein (0)
 

3xTgAD Protein (0.0523452)
ECHS1, ALDH1A3, AACS, ACAT1, MYO5B, DCXR, HMGCS1.

E.18. Synthesis and Degradation of Ketone Bodies (Enrichment Ratio*−log10(𝑝))

Control Protein (0)
 

3xTgAD Protein (0.071505)
ACAT1, HMGCS1.

F.

Cellular stress/damage pathway clusters of extracted proteins from primary cortical tissue. Specific energy cellular stress/damage pathway clusters generated in an un-biased manner using Ingenuity Pathway Analysis (v. 8.5). The relative score generated for the degree of pathway population by proteins from the respective input sets (control or 3xTgAD) is shown in bold. The following are different types of signaling pathways.

F.1. NRF2-mediated Oxidative Stress Response (Enrichment Ratio*−log10(𝑝))

Control Protein (0.44064)
PRDX1, PPIB, GCLC, PRKCZ, GSTM2, SOD2, PIK3CG, VCP, DNAJA2, TXN, FKBP5, PRKD1, CBR1, PRKCA, GSTK1, SOD1, PRKCQ, TXNRD1, GSTO1, FOS, PRKCI, ERP29, STIP1, CAT, PRKCB, EPHX1.

3xTgAD Protein (0.23751)
USP14, SOD1, PRDX1, ACTB, GSTM3 (includes EG:2947), JUNB, DNAJC5, GSTM2, SOD2, ERP29, STIP1, PIK3C3, PRKCD, ABCC1, VCP, PIK3CB, FOSL1, PIK3R2, TXN, EIF2AK3, ACTA1.

F.2. Ceramide Signaling (Enrichment Ratio*−log10(𝑝))

Control Protein (0.15748)
CTSD, PPP2CB, FOS, PPP2R1A, PPP2R2A, PIK3CG, PPP2R2B, PPP2R5E, PPP2R1B.

3xTgAD Protein (0)
 

F.3. Glutathione Metabolism (Enrichment Ratio*−log10(𝑝))

Control Protein (0.094285)
OPLAH, PGD, GSTM2, GGT5, GCLC, GGT1, GSTO1, GSTK1, GGT7.

3xTgAD Protein (0)
 

F.4. LPS/IL-1 Mediated Inhibition of RXR Function (Enrichment Ratio*−log10(𝑝))

Control Protein (0.19071)
SULT1C2, FMO3, CPT1A, CHST7, ALDH1L1, NR1H3, GSTO1, SULT4A1, GSTM2, NR1I2, SREBF1, SULT1A1, CAT, CPT2, FABP4, XPO1, FABP1, FABP7, SULT1E1, FABP3, GSTK1, TLR4, FABP2.

3xTgAD Protein (0.13872)
PPARA, GSTM3 (includes EG:2947), ABCA1, IL1R2, ABCC2, SLC27A5, GSTM2, ALDH1A3, NR1I2, CPT2, ACSL4, FABP1, IL1B, NR5A2, CHST10, LBP, ABCC4, HMGCS1, ACSL1, MAOA.

F.5. Fatty Acid Elongation in Mitochondria (Enrichment Ratio*−log10(𝑝))

Control Protein (0)
 

3xTgAD Protein (0.0206016)
ECHS1, PECR

F.6. Endoplasmic Reticulum Stress Pathway (Enrichment Ratio*−log10(𝑝))

Control Protein (0)
 

3xTgAD Protein (0.047841)
EIF2AK3, CASP7.

F.7. Apoptosis Signaling (Enrichment Ratio*−log10(𝑝))

Control Protein (0)
 

3xTgAD Protein (0.059156)
ACIN1, ROCK1, CAPN5, CAPN6, CAPN1, BAX, CASP7, PARP1.

F.8. Hypoxia Signaling (Enrichment Ratio*−log10(𝑝))

Control protein (0)
 

3xTgAD Protein (0.111983)
VEGFA, P4HB, HSP90AB1, UBE2L3, NOS3, UBC, ARNT, ATM.

F.9. PPARα/RXRα Activation (Enrichment Ratio*−log10(𝑝))

Control Protein (0.0315615)
PDIA3, PRKAR2A, NR2C2, SHC1, PRKAR2B, TGFB1, FASN, PRKACA, PLCB1, GOT2, PLCL1, PRKCB, PRKCA, PRKAR1A.

3xTgAD Protein (0.14586)
PPARA, ACVR1, PRKAR2A, CD36, IL6, JAK2, ABCA1, IL1R2, ACADL, HSP90AB1, TGFB1, IRS1, PRKACA, SMAD4, IL1B, ADCY8, PLCD4, PRKAR1A.

G.

Receptor signaling pathway clusters of extracted proteins from primary cortical tissue. Specific receptor signaling pathway clusters generated in an un-biased manner using Ingenuity Pathway Analysis (v. 8.5). The relative score generated for the degree of pathway population by proteins from the respective input sets (control or 3xTgAD) is shown in bold. The following are different types of signaling pathways.

G.1. Dopamine Receptor Signaling

Control Protein (0.65824)
PPP2R2A, PRKAR2A, PPP1R14B, PPP2CB, PPP2R1A, PRKAR2B, PPP1R10, PPP1R14D, PPP1R7, PPP2R2B, PRKACA, FREQ, PPP2R5E, PPP2R1B, PRKAR1A, CALY.

3xTgAD Protein (0.071199)
PPP2R1A, FREQ, PRKAR2A, PRKACA, ADCY8, CALY, MAOA, PRKAR1A.

G.2. PDGF Signaling

Control Protein (0.73892)
SRC, CRKL, CRK, STAT3, FOS, SHC1, PIK3CG, CSNK2A1, PDGFRA, CAV1, CSNK2B, ELK1, STAT1, PRKCB, PRKCA.

3xTgAD Protein (0.15738)
MYC, JAK1, PIK3C3, STAT3, PIK3R2, JAK2, ELK1, INPP5D.

G.3. EGF Signaling

Control Protein (0.7956)
SHC1, FOS, PIK3CG, CSNK2A1, EGF, CSNK2B, STAT3, STAT1, ELK1, PRKCA, EGFR.

3xTgAD Protein (0.22499)
JAK1, PIK3C3, PIK3CB, STAT3, PIK3R2, ELK1, EGFR.

G.4. Neuregulin Signaling

Control Protein (0.68068)
SRC, PRKCQ, CRKL, EGF, CRK, ERBB3, PRKCZ, SHC1, PRKCI, PTPN11, ERBB4, CDKN1B, ELK1, PRKD1, PRKCB, EGFR, PRKCA.

3xTgAD Protein (0.1276)
MYC, STAT5A, MTOR, PTPN11, HSP90AB1, PRKCD, PIK3R2, CDKN1B, ELK1, EGFR.

G.5. Glutamate Receptor Signaling

Control Protein (0.53342)
GRM5, GRIN2B, GRIN2A, GRIK4, GRIA1, GRID2, CALM2, GLUL, GRIP1, GRM4, GNG7, GRIK1.

3xTgAD Protein (0)
 

G.6. Sonic Hedgehog Signaling

Control Protein (0.73272)
SHH, CCNB1, PRKAR2B, PRKAR2A, PRKACA, SMO, GLI1, PRKAR1A.

3xTgAD Protein (0.20769)
ADRBK1, PTCH1, PRKAR2A, PRKACA, PRKAR1A.

G.7. TR/RXR Activation

Control Protein (0.5481)
UCP2, RCAN2, UCP1, THRA, GRIP1, PFKP, PCK1, KLF9, SREBF1, DIO1, FASN, PIK3CG, STRBP, THRB, FGA, SYT12.

3xTgAD Protein (0.0321142)
MTOR, PIK3C3, STRBP, ACACA, PIK3CB, PIK3R2, THRB.

G.8. Ephrin Receptor Signaling

Control Protein (0.62472)
GRIN2A, CDC42, EGF, CRK, GNG7, PGF, VEGFA, PTK2, SHC1, PAK1, SDC2, PIK3CG, EFNB1, EPHA7, GRIN2B, SRC, PAK2, CFL1, CRKL, EPHA3, STAT3, WIPF1, SDCBP, PTPN11, PAK3, EPHA5, EPHB3.

3xTgAD Protein (0.21037)
FYN, PXN, CFL1, CDC42, KALRN, GNB2L1, GNAI1, RAC1, JAK2, STAT3, GNAZ, ROCK1, VEGFA, GNAI2, ROCK2, ABI1, PTPN11, PAK3, RHOA, GNAO1.

G.9. G-Protein Coupled Receptor Signaling

Control Protein (0.3808)
PDE7A, PDE4A, PDE1A, PDE4D, SHC1, SYNGAP1, PDE7B, PIK3CG, PLCB1, PRKCA, SRC, GRK4, EDNRB, PDE10A, PRKAR2A, PDE4B, STAT3, GRM4, PDE1C, CHRM5, GRM5, OPRD1, PRKAR2B, PRKACA, PRKCB, PRKAR1A.

3xTgAD Protein (0.13938)
FYN, PTK2B, HTR4, ADRBK1, PDE10A, RGS7, PRKAR2A, GNAI1, RGS4, STAT3, PDE4B, GNAI2, HTR2C, PIK3C3, GNAO1, PRKACA, PIK3CB, PIK3R2, ADCY8, PRKAR1A.

G.10. Chemokine Signaling

Control Protein (0.23961)
PTK2, NOX1, SRC, FOS, CCL4, CFL1, PIK3CG, CALM2, PLCB1, PRKCA, PRKCB.

3xTgAD Protein (0.03232)
ROCK2, GNAI2, CFL1, PTK2B, RHOA, GNAI1.

G.11. Ceramide Signaling

Control Protein (0.15748)
CTSD, PPP2CB, FOS, PPP2R1A, PPP2R2A, PIK3CG, PPP2R2B, PPP2R5E, PPP2R1B, PRKCZ.

3xTgAD protein (0)
 

G.12. FGF (Fibroblast Growth Factor) Signaling

Control Protein (0.17423)
FGFR3, PTPN11, FGF18, CRKL, PIK3CG, FGFR1, FGF23, FGFR2, CRK, STAT3, PRKCA.

3xTgAD Protein (0.0667352)
PTPN11, PIK3C3, HGF, RAC1, PIK3CB, STAT3, PIK3R2, MAPKAPK2.

G.13. Toll-like Receptor Signaling

Control Protein (0.1644)
TLR4, FOS, TLR5, TLR6, TLR3, ELK1, TLR9.

3xTgAD Protein (0.065562)
PPARA, TLR5, MAP3K7IP2, LBP, ELK1.

G.14. Nitric Oxide Signaling

Control Protein (0.41157)
GUCY1B2, GUCY1A3, GUCY2D, CALM2, PRKAR2A, PGF, VEGFA, PRKAR2B, PIK3CG, GUCY1A2, CAV1, PRKACA, PRKAR1A.

3xTgAD Protein (0.36801)
VEGFA, HSP90AB1, GUCY2D, PRKCD, PIK3C3, GUCY2F, PRKAR2A, PRKACA, PIK3CB, PIK3R2, NOS3, PRKAR1A.

G.15. cAMP-Mediated Signaling

Control Protein (0.39295)
GRK4, SRC, CNGA4, PDE7A, PDE10A, PRKAR2A, CALM2, PDE4A, PPP3CC, STAT3, PDE4B, GRM4, PDE1A, PDE4D, CNGA1, PDE1C, CHRM5, OPRD1, PRKAR2B, PDE7B, PRKACA, PKIA, PRKAR1A.

3xTgAD Protein (0.40848)
AKAP12, HTR4, ADRBK1, PDE10A, RGS7, PRKAR2A, GNAI1, RGS4, AKAP3, PPP3CC, STAT3, PDE4B, CNGA1, GNAI2, AKAP4, GNAO1, PRKACA, CNGB1, PKIA, ADCY8, AKAP9, PRKAR1A.

G.16. TGF-β Signaling

Control protein (0)
 

3xTgAD Protein (0.0236421)
TGFB1, ACVR1, SMAD4, HNF4A, UBC, INHBC.

G.17. Neurotrophin/TRK Signaling

Control Protein (0.016851)
SHC1, FOS, CDC42, PTPN11, PIK3CG.

3xTgAD Protein (0.0440592)
NTRK2, CDC42, PTPN11, PIK3C3, PIK3CB, PIK3R2.

G.18. IGF-1 Signaling

Control Protein (0.49715)
PRKAR2A, PTK2, SHC1, FOS, PRKAR2B, PTPN11, PIK3CG, PRKACA, CSNK2A1, CSNK2B, ELK1, PRKAR1A.

3xTgAD Protein (0.52722)
PXN, YWHAH, PRKAR2A, NEDD4, YWHAQ, PTPN11, IRS1, PIK3C3, PRKACA, IGF1R, IRS2, PIK3CB, PIK3R2, ELK1, PRKAR1A.

G.19. Serotonin Receptor Signaling

Control protein (0)
 

3xTgAD Protein (0.059769)
HTR2C, HTR4, HTR3A, MAOA.

G.20. Glucocorticoid Receptor Signaling

Control protein (0)
 

3xTgAD Protein (0.066)
STAT5A, JAK1, YWHAH, HSPA14, RAC1, IL6, PPP3CC, STAT3, JAK2, NFKB1, MNAT1, IL1R2, HSP90AB1, TGFB1, PIK3C3, CEBPA, PRKACA, SMAD4, IL1B, PIK3CB, PIK3R2, ELK1.

G.21. Aryl Hydrocarbon Receptor Signaling

Control Protein (0.1218)
SRC, CDK6, ALDH1L1, GSTO1, TGM2, CTSD, FOS, GSTM2, TGFB1, FASN, CDKN1B, ESR2, CDK2, FASLG, ATM, GSTK1.

3xTgAD Protein (0.31125)
CYP1A1, NFIX, GSTM3, IL6, BAX, NFKB1, ARNT, MYC, AHRR, GSTM2, CCND2, HSP90AB1, TGFB1, ALDH1A3, IL1B, CDKN1B, AHR, MCM7, ATM.

G.22. Insulin Receptor Signaling

Control Protein (0.28288)
TSC1, TRIP10, CRKL, PRKAR2A, CRK, VAMP2, PPP1R14B, PRKCZ, SHC1, PRKCI, PPP1R10, PTPN11, PIK3CG, TSC2, PRKACA.

3xTgAD Protein (0.5056)
TSC1, FYN, JAK1, PRKAR2A, JAK2, VAMP2, INPP5D, MTOR, PTPN11, IRS1, PIK3C3, PRKACA, EIF2B1, PIK3CB, IRS2, PIK3R2, PRKAR1A.

G.23. Notch Signaling

Control Protein (0.0437248)
DLL1, CNTN1, NCSTN, DLL3.

3xTgAD Protein (0.30609)
NOTCH4, DLL1, NOTCH2, NCSTN, JAG1, NOTCH1, HEY1.

G.24. GABA Receptor Signaling

Control Protein (0.099214)
GABRG2, UBQLN1, GABBR1, GABARAP, UBC, GABRA3.

3xTgAD Protein (0.4216)
DNM1, NSF, SLC32A1, UBQLN1, GABBR1, MYO5B, GABRE, UBC, GABRA3.

G.25. VEGF Signaling

Control Protein (0.0252652)
VEGFA, PTK2, SHC1, PIK3CG, PGF, PRKCA, PRKCB.

3xTgAD Protein (0.53464)
EIF2S2, PXN, PTK2B, ACTB, NOS3, ARNT, ROCK2, VEGFA, ROCK1, PIK3C3, EIF2B1, PIK3CB, PIK3R2, ACTN4, ACTA1.

G.26. Integrin Signaling

Control protein (0)
 

3xTgAD Protein (0.54604)
RAP2B, FYN, RALA, CDC42, TSPAN3, ARF6, RHOB, PIK3C3, ARF4, PIK3R2, ACTA1, CAPN5, CAPN6, PXN, ACTB, RALB, RAC1, ITGA6, RHOJ.

H.

Heatmap Protein Position Key
The individual position numbers are correlated to the specific multidimensional proteins represented by colored blocks in Figure 6. The following are the symbols of the proteins (the numbers between brackets refer to the position).(1)adcyap1: adenylate cyclase activating polypeptide 1 (pituitary)(2)adcyap1r1: adenylate cyclase activating polypeptide 1 (pituitary) receptor type I(3)hap1: huntingtin-associated protein 1(4)htr4: 5-hydroxytryptamine (serotonin) receptor 4(5)ntrk2: neurotrophic tyrosine kinase, receptor, type 2(6)Kalrn: kalirin, RhoGEF kinase(7)klc1: kinesin light chain 1(8)adrbk1: adrenergic, beta, receptor kinase 1(9)agrn: agrin(10)apod: apolipoprotein D(11)app: amyloid beta (A4) precursor protein(12)arhgef11: Rho guanine nucleotide exchange factor (GEF) 11(13)arpp19: cAMP-regulated phosphoprotein, 19 kDa(14)bace1: beta-site APP-cleaving enzyme 1(15)ccs: copper chaperone for superoxide dismutase(16)chgb: chromogranin B (secretogranin 1)(17)flot1: flotillin 1(18)flot2: flotillin 2(19)gnb2l1: guanine nucleotide binding protein (G protein), beta polypeptide 2-like 1(20)hyou1: hypoxia up-regulated 1(21)lphn1: latrophilin 1(22)lphn2: latrophilin 2(23)magi3: membrane associated guanylate kinase, WW and PDZ domain containing 3(24)nefh: neurofilament, heavy polypeptide(25)prdx6: peroxiredoxin 6(26)pscd2: cytohesin 2(27)rtn3: reticulon 3(28)rtn4r: reticulon 4 receptor(29)slc44a4: solute carrier family 44, member 4(30)stxbp1: syntaxin binding protein 1(31)abca1: ATP-binding cassette, sub-family A (ABC1), member 1(32)abi1: abl-interactor 1(33)adcy1: adenylate cyclase 1 (brain)(34)adcy5: adenylate cyclase 5(35)akap9: A kinase (PRKA) anchor protein 9(36)aldh1a3: aldehyde dehydrogenase 1 family, member A3(37)alox5: arachidonate 5-lipoxygenase(38)arf6: ADP-ribosylation factor 6(39)arhgef12: Rho guanine nucleotide exchange factor (GEF) 12(40)atcay: ataxia, cerebellar, Cayman type(41)atp2b1: ATPase, Ca++ transporting, plasma membrane 1(42)atxn3: ataxin 3(43)begain: brain-enriched guanylate kinase-associated homolog (rat)(44)cabc1: chaperone, ABC1 activity of bc1 complex homolog (S. pombe)(45)capn1: calpain 1, (mu/l) large subunit(46)caskin1: CASK interacting protein 1(47)casp7: caspase 7, apoptosis-related cysteine peptidase(48)cd36: CD36 molecule (thrombospondin receptor)(49)cfd: complement factor D (adipsin)(50)clu: clusterin(51)cpa2: carboxypeptidase A2 (pancreatic)(52)cript: cysteine-rich PDZ-binding protein(53)dpp6: dipeptidyl-peptidase 6(54)espn: espin(55)fdps: farnesyl diphosphate synthase(56)filip1: filamin A interacting protein 1(57)gna11: guanine nucleotide binding protein (G protein), alpha 11 (Gq class)(58)gnai2: guanine nucleotide binding protein (G protein), alpha inhibiting activity polypeptide 2(59)gnao1: guanine nucleotide binding protein (G protein), alpha activating activity polypeptide O(60)gnaq: guanine nucleotide binding protein (G protein), q polypeptide(61)gnaz: guanine nucleotide binding protein (G protein), alpha z polypeptide(62)gpr56: G protein-coupled receptor 56(63)hip1r: huntingtin interacting protein 1 related(64)hmgcr: 3-hydroxy-3-methylglutaryl-Coenzyme A reductase(65)hsf1: heat shock transcription factor 1(66)htr2c: 5-hydroxytryptamine (serotonin) receptor 2C(67)itm2c: integral membrane protein 2C(68)itpr3: inositol 1,4,5-triphosphate receptor, type 3(69)lsamp: limbic system-associated membrane protein(70)maoa: monoamine oxidase A(71)map1lc3a: microtubule-associated protein 1 light chain 3 alpha(72)mapkapk2: mitogen-activated protein kinase-activated protein kinase 2(73)mark1: MAP/microtubule affinity-regulating kinase  1(74)mdga2: MAM domain containing glycosylphosphatidylinositol anchor 2(75)mpdz: multiple PDZ domain protein(76)mpo: myeloperoxidase(77)mpp7: membrane protein, palmitoylated 7 (MAGUK p55 subfamily member 7)(78)ncam1: neural cell adhesion molecule 1(79)ncam2: neural cell adhesion molecule 2(80)ncdn: neurochondrin(81)ndufs1: NADH dehydrogenase (ubiquinone) Fe-S protein 1, 75 kDa (NADH-coenzyme Q reductase)(82)ndufs7: NADH dehydrogenase (ubiquinone) Fe-S protein 7, 20 kDa (NADH-coenzyme Q reductase)(83)nes: nestin(84)nlgn2: neuroligin 2(85)nlgn3: neuroligin 3(86)npc2: Niemann-Pick disease, type C2(87)npdc1: neural proliferation, differentiation and control, 1(88)npy5r: neuropeptide Y receptor Y5(89)nsf: N-ethylmaleimide-sensitive factor(90)padi2: peptidyl arginine deiminase, type II(91)plcb4: phospholipase C, beta 4(92)pxn: paxillin(93)rab5a: RAB5A, member RAS oncogene family(94)rgs4: regulator of G-protein signaling 4(95)rgs7: regulator of G-protein signaling 7(96)rims1: regulating synaptic membrane exocytosis 1(97)rora: RAR-related orphan receptor A(98)sh3gl1: SH3-domain GRB2-like 1(99)sod2: superoxide dismutase 2, mitochondrial(100)sst: somatostatin(101)vldlr: very low density lipoprotein receptor(102)camkk1: calcium/calmodulin-dependent protein kinase kinase 1, alpha(103)cacna2d2: calcium channel, voltage-dependent, alpha 2/delta subunit 2(104)vcp: valosin-containing protein(105)stx1a: syntaxin 1A (brain)(106)vgf: VGF nerve growth factor inducible(107)calb2: calbindin 2(108)prdx1: peroxiredoxin 1(109)stmn2: stathmin-like 2(110)vsnl1: visinin-like 1(111)cdh2: cadherin 2, type 1, N-cadherin (neuronal)(112)dbn1: drebrin 1(113)oxr1: oxidation resistance 1(114)gpsm1: G-protein signaling modulator 1 (AGS3-like, C. elegans)(115)gmfb: glia maturation factor, beta(116)cd2ap: CD2-associated protein(117)centa1: ArfGAP with dual PH domains 1(118)ncstn: nicastrin(119)pak3: p21 protein (Cdc42/Rac)-activated kinase 3(120)sncb: synuclein, beta(121)calb1: calbindin 1(122)cnr1: cannabinoid receptor 1 (brain)(123)disc1: disrupted in schizophrenia 1(124)dlgap2: discs, large (Drosophila) homolog-associated protein 2(125)dlgap4: discs, large (Drosophila) homolog-associated protein 4(126)dtnb: dystrobrevin, beta(127)dvl1: dishevelled, dsh homolog 1 (Drosophila)(128)exoc7: exocyst complex component 7(129)gabbr1: gamma-aminobutyric acid (GABA) B receptor, 1(130)panx1: pannexin 1(131)pclo: piccolo (presynaptic cytomatrix protein)(132)phactr3: phosphatase and actin regulator 3(133)picalm: phosphatidylinositol binding clathrin assembly protein(134)shank1: SH3 and multiple ankyrin repeat domains 1(135)snap91: synaptosomal-associated protein, 91 kDa homolog (mouse)(136)stmn4: stathmin-like 4(137)sod1: superoxide dismutase 1, soluble(138)synj2: synaptojanin 2(139)tub: tubby homolog (mouse)(140)snca: synuclein, alpha (non A4 component of amyloid precursor)(141)park7: Parkinson disease (autosomal recessive, early onset) 7(142)pcsk1n: proprotein convertase subtilisin/kexin type 1 inhibitor(143)palm: Paralemmin(144)vapb: VAMP (vesicle-associated membrane protein)-associated protein B and C(145)cttn: cortactin(146)cacna1a: calcium channel, voltage-dependent, P/Q type, alpha 1A subunit(147)celsr3: cadherin, EGF LAG seven-pass G-type receptor 3 (flamingo homolog, Drosophila)(148)chl1: cell adhesion molecule with homology to L1CAM (close homolog of L1)(149)chrm5: cholinergic receptor, muscarinic 5(150)cnksr2: connector enhancer of kinase suppressor of Ras 2(151)cnp: 2^',3^'-cyclic nucleotide 3^' phosphodiesterase(152)cntfr: ciliary neurotrophic factor receptor(153)cntn1: contactin 1(154)cplx1: complexin 1(155)dag1: dystroglycan 1 (dystrophin-associated glycoprotein 1)(156)dbndd2: dysbindin (dystrobrevin binding protein 1) domain containing 2(157)dbnl: drebrin-like(158)dclk2: doublecortin-like kinase 2(159)dlgap1: discs, large (Drosophila) homolog-associated protein 1(160)dscam: Down syndrome cell adhesion molecule(161)ecel1: endothelin converting enzyme-like 1(162)efnb1: ephrin-B1(163)eml5: echinoderm microtubule associated protein like 5(164)epha3: EPH receptor A3(165)epha5: EPH receptor A5(166)epha7: EPH receptor A7(167)ephb3: EPH receptor B3(168)erbb4: v-erb-a erythroblastic leukemia viral oncogene homolog 4 (avian)(169)evl: Enah/Vasp-like(170)exoc5: exocyst complex component 5(171)fzd9: frizzled homolog 9 (Drosophila)(172)GABARAP: GABA(A) receptor-associated protein(173)gabarapl2: GABA(A) receptor-associated protein-like  2(174)gabrr3: gamma-aminobutyric acid (GABA) A receptor, alpha 3(175)gcgr: glucagon receptor(176)gng7: guanine nucleotide binding protein (G protein), gamma 7(177)got1: glutamic-oxaloacetic transaminase 1, soluble (aspartate aminotransferase 1)(178)got2: glutamic-oxaloacetic transaminase 2, mitochondrial (aspartate aminotransferase 2)(179)gprc6a: G protein-coupled receptor, family C, group 6, member A(180)gria1: glutamate receptor, ionotropic, AMPA 1(181)grid2: glutamate receptor, ionotropic, delta 2(182)grik4: glutamate receptor, ionotropic, kainate 4(183)grin2a: glutamate receptor, ionotropic, N-methyl D-aspartate 2A(184)grip1: glutamate receptor interacting protein 1(185)gripap1: GRIP1 associated protein 1(186)grk6: G protein-coupled receptor kinase 6(187)opa1: optic atrophy 1 (autosomal dominant)(188)pak1: p21 protein (Cdc42/Rac)-activated kinase 1(189)pak2: p21 protein (Cdc42/Rac)-activated kinase 2(190)pawr: PRKC, apoptosis, WT1, regulator(191)phactr1: phosphatase and actin regulator 1(192)pip5k1c: phosphatidylinositol-4-phosphate 5-kinase, type I, gamma(193)plcb1: phospholipase C, beta 1 (phosphoinositide-specific)(194)pld3: phospholipase D family, member 3(195)ppfia3: protein tyrosine phosphatase, receptor type, f polypeptide (PTPRF), interacting protein (liprin), alpha 3(196)ppid: peptidylprolyl isomerase D(197)ppp2cb: protein phosphatase 2 (formerly 2A), catalytic subunit, beta isoform(198)ppp2r2a: protein phosphatase 2 (formerly 2A), regulatory subunit B, alpha isoform(199)prkar2b: protein kinase, cAMP-dependent, regulatory, type II, beta(200)prnp: prion protein(201)ptk2: PTK2 protein tyrosine kinase 2(202)ptn: pleiotrophin(203)ryr3: ryanodine receptor 3(204)sdcbp: syndecan binding protein (syntenin)(205)sh3gl3: SH3-domain GRB2-like 3(206)shank2: SH3 and multiple ankyrin repeat domains 2(207)sirt2: sirtuin (silent mating type information regulation 2 homolog) 2 (S. cerevisiae)(208)smu1: smu-1 suppressor of mec-8 and unc-52 homolog (C. elegans)(209)soat1: sterol O-acyltransferase 1(210)sstr2: somatostatin receptor 2(211)ssx2ip: synovial sarcoma, X breakpoint 2 interacting protein(212)stau1: staufen, RNA binding protein, homolog 1 (Drosophila)(213)stmn3: stathmin-like 3(214)strn: striatin, calmodulin binding protein(215)syn1: synapsin I(216)syngap1: synaptic Ras GTPase activating protein 1 homolog (rat)(217)synj2bp: synaptojanin 2 binding protein(218)synpo: synaptopodin(219)syt11: synaptotagmin XI(220)trap1: TNF receptor-associated protein 1(221)trpc2: transient receptor potential cation channel, subfamily C, member 2 (pseudogene)(222)trpc4: transient receptor potential cation channel, subfamily C, member 4(223)trpc5: transient receptor potential cation channel, subfamily C, member 5(224)wnt7a: wingless-type MMTV integration site family, member 7A(225)tuba1a: tubulin, alpha 1a(226)vipr2: vasoactive intestinal peptide receptor 2(227)trak2: trafficking protein, kinesin binding 2(228)snx17: sorting nexin 17(229)psd: pleckstrin and Sec7 domain containing(230)ppp2r2b: protein phosphatase 2 (formerly 2A), regulatory subunit B, beta isoform(231)ppp1r9b: protein phosphatase 1, regulatory (inhibitor) subunit 9B(232)grm5: glutamate receptor, metabotropic 5(233)grk5: G protein-coupled receptor kinase 5(234)grin2b: glutamate receptor, ionotropic, N-methyl D-aspartate 2B(235)grik1: glutamate receptor, ionotropic, kainate 1(236)grasp: GRP1 (general receptor for phosphoinositides 1)-associated scaffold protein(237)gipc1: GIPC PDZ domain containing family, member  1(238)dpysl4: dihydropyrimidinase-like 4(239)dpysl3: dihydropyrimidinase-like 3(240)dgkb: diacylglycerol kinase, beta 90 kDa(241)ddn: dendrin(242)cit: citron (rho-interacting, serine/threonine kinase 21)(243)grm4: glutamate receptor, metabotropic 4(244)ctnnd2: catenin (cadherin-associated protein), delta 2 (neural plakophilin-related arm-repeat protein).

I.

Receptor-specific protein interaction networks in lipid raft extracts from control animals. IPA-generated receptor-specific protein lists from control lipid raft samples were clustered into coherent functional interaction networks. Focus molecules (BOLD in “molecules in network”) denote the proteins that are present in the predicted reaction network as well as the experimental input protein set. The following are different types of interaction networks.

(1) Control: cell signaling, nucleic acid metabolism, small molecule biochemistry; score: 32; focus molecule: 15; molecules in network: ADCY, Akt, Beta-Arrestin, CD4, CHRM5, CNTFR, Creb, EDNRB, ERK1/2, FSHR, GABBR1, GCGR, Gpcr, GPR3, GPR12, GPR20, GPR34, GPR65, GPR161, GRM5, hCG, Mapk, OPRD1, OVGP1, P2RY6, P2RY11, PDGF BB, PI3K, Pkc(s), PTGER2, SFRP4, SSTR2, THBD, UNC5B, VIPR2.

(2) Control: infectious disease, antigen presentation, antimicrobial response; score: 31; focus molecule: 15; molecules in network: Ap1, CHRNB3, CHRNB4, CHRNG, CLDN4, CNR1, CXADR, G alphai, Ifn, IFN Beta, IFN TYPE 1, IgG, IKK (complex), IL-1R/TLR, IL12 (complex), Il12 (family), Interferon alpha, IRAK, IRF, NFkB (complex), NRG, OSMR, P38 MAPK, SMO, TACR1, Tlr, TLR3, TLR4, TLR5, TLR6, TLR9, TSHR, Ubiquitin.

(3) Control: cellular development tumor morphology, cell death; score: 18; focus molecule: 10; molecules in network: APOL5, ARR3, ARTN, ASB16, Cadherin (E,N,P,VE), CELSR2, CELSR3, CTNNB1, CTNNβ-CDHE/N, DAG1, EVX1, FZD9, GDNF, GFRA1, GFRA3, GLTSCR1, GPRC6A, GRB2, GRM4, HRH4, KCNN1, OPN1LW, OPN1SW, PALM2-AKAP2, PHACTR2, PRICKLE3, PTH2R, SAG, SEPN1, SHROOM2, SRC.

(4) Control: carbohydrate metabolism; score: 2; focus molecule: 1; molecules in network: CLEC4A, IL13.

(5) Control: cell-to-cell signaling and interaction, nervous system development and function; score: 2; focus molecule: 1; molecules in network: PRPH2, ROM1.

(6) Control: protein synthesis, molecular transport, protein trafficking; score: 2; focus molecule: 1; molecules in network: GABRR3, PRKCZ, SQSTM1.

J.

Receptor-specific protein interaction networks in lipid raft extracts from 3xTgAD animals. IPA-generated receptor-specific protein lists from 3xTgAD lipid raft samples were clustered into coherent functional interaction networks. Focus molecules (BOLD in “molecules in network”) denote the proteins that are present in the predicted reaction network as well as the experimental input protein set. The following are different types of interaction networks.

(1) 3xTgAD: metabolic disease, endocrine system disorders, cell signaling; score: 45; focus molecule: 18; molecules in network: ADCYAP1R1, Ap1, CD36, CD86, CNR1, Creb, CREB-NFkB, CXADR, ERK, ERK1/2, GABBR1, GPR56, hCG, HTR4, HTR2C, IGF1R, IGF2R, IgG, IL12 (complex), IL1R2, Insulin, Jnk, LDL, LIFR, LRPAP1, Mapk, MIP1, NFkB (complex), NPR2, OVGP1, P38 MAPK, Pkc(s), TLR5, TNFRSF14, TSHR.

(2) 3xTgAD: cell signaling, nucleic acid metabolism, small molecule biochemistry; score: 13; focus molecule: 7; molecules in network: AATK, ABR, AKR1A1, BPI, CACNG5, CRYM, cyclic AMP, CYP26B1, DHRS3, DLG4, GH1, Histone h3, HSD17B11, KCTD11, KIF3C, LAP3, LPHN1, LPHN2, OPN1LW, OPN1SW, P2RY11, PTCH1, PTH2R, RLN3, RN5S, ROBO1, ROS1, RXFP1, RXFP2, SERPINB8, TMEM49, TNF, USP3.

(3) 3xTgAD: cell signaling, cellular function and maintenance, molecular transport; score: 2; focus molecule: 1; molecules in network: CFTR, FREQ, IL1RAPL1, MYD88.

(4) 3xTgAD: cell-to-cell signaling and interaction, cellular function and maintenance, cellular movement; score: 2; focus molecule: 1; molecules in network: GPR1, PAX3, PRDM5.

(5) 3xTgAD: behavior, digestive system development and function, cell morphology; score: 2; focus molecule: 1; molecules in network: NPY, NPY5R, PPY, PYY, SSB.

(6) 3xTgAD: cancer, reproductive system disease, gene expression; score: 2; focus molecule: 1; molecules in network: FOS, MIR103-1, MIR103-2, MIR107, MIRLET7G, MYC, OMG, RHOA, RTN4R.

Acknowledgments

This work was carried out with the support of the Intramural Research Program of the National Institute on Aging, National Institutes of Health. The authors thank Dr. LaFerla for kindly donating 3xTgAD breeding pairs to the National Institute on Aging.

Supplementary Materials

Supplementary Table 1: the table illustrates the top 50 most upregulated and top 50 most downregulated (italics) proteins (commonly identified in 3xTgAD and control WT) in 3xTgAD cortical raft extracts compared to WT.

Ranking was based on relative expression ratios generated by spectral counting for 3xTgAD:WT proteins that displayed a >95% identity confidence.

Proteins ranked 1-50 for 3xTgAD>WT (increased in 3xTgAD compared to WT) represent those with expression ratios (3xTgAD:WT) greater than unity while proteins ranked 1-50 for WT>3xTgAD (decreased in 3xTgAD compared to WT: italics) represents those with expression ratios (3xTgAD:WT) less than unity. In each case the most up or downregulated proteins are ranked 1.

1. Supplementary Table