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| Organoid type/brain regions | Disease | References | Main discovery |
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| Human forebrain organoid | FXS organoids with | [6] | Dysregulated neurogenesis, neuronal maturation, and neuronal excitability in the forebrain loss of FMRP. Inhibition of the PI3K signaling could rescue developmental deficit of the FXS forebrain organoids |
| Cortical brain organoid cortical organoids | FXS | [73] | Increased number of glial cells, and bigger organoid size compared to normal person |
| Cortical brain organoid | FXS | [74] | FXS organoids bear higher percentage of Ki67+SOX2+ proliferative cells PI3K functions as a key driver of downstream dysregulation of both translations and cell proliferation in early NPCs. |
| Cerebral organoid | ALS/FTD | [142] | Recapitulates mature cortical architecture and early molecular pathology of C9ORF72 ALS/FTD. Increased levels of the autophagy signaling protein P62 in astroglia.
Accumulation of DNA damage, poly(GA), and nuclear pyknosis in deep layer neurons |
| Sensorimotor organoid | ALS | [143] | Diversity of neuronal derivatives, such as motor, sensory neurons, astrocytes, and mesodermal derivatives, including vasculature, microglia, and skeletal muscle. The NMJs connect the motor neurons and skeletal muscle, but the NMJs were defected in ALS organoids. Altered ability for deriving the NMJ synapse and cell diversity that exert autonomous and noncell autonomous effects on motor neurons |
| Schizophrenia (Scz) cerebral | | [144] | In the Scz organoids, the progenitor survival significantly changed led to disruption of neurogenesis, ultimately generating fewer neurons within developing cortical fields compared to the normal organoids. |
| Cerebral organoids (iCOs) | AD | [145] | Miniaturized AD pathological models and CRISPR-Cas9-edited isogenic lines established a high-content screening (HCS) system, and the FDA-approved drugs were tested for the blood–brain barrier-permeability |
| Cerebral organoids whole brain | AD | [38] | The organoids from patients affected by familial AD or DS displayed pathological features of AD, such as accumulation of structures like amyloid plaques and neurofibrillary tangles, but nondetectable in the control organoids. |
| Cerebral organoids whole brain | AD | [53] | Significant apoptosis, impaired synaptic integrity, enhanced stress granules and disrupted RNA metabolism were detected in cerebral organoids (CO) with APOE ε4/ε4 genotype from AD patients.
Conversion of APOE4 to APOE3 ameliorated the APOE4-associated phenotypes in Cos from AD patients. APOE4-related degenerative pathways were assumed to contribute to AD pathogenesis. |
| Cerebral organoids whole brain | AD | [56] | CKD-504, a highly BBB-penetrating HDAC6 inhibitor, significantly reduced tau via acetylation in AD patient-iPSC-derived brain organoids, dramatically attenuating pathological tau and ultimately rescuing the synaptic pathologies |
| Cerebral organoids whole brain | AD | [48] | Cerebral organoids (Cos) generated from PITRM1-KO iPSCs recapitulated AD pathological features such as the accumulation of protein aggregates, tau pathology, and neuronal cell death. ScRNA-seq discovered mitochondrial function defect in all cell types in COs with PITRM1-KO.
PITRM1-linked neurodegeneration caused by defects of mitochondrial presequence processing induce an early activation of UPRmt, supporting a mechanistic link between mitochondrial function and common neurodegenerative proteinopathies. |
| Cerebral organoids whole brain | AD | [46] | Compared with the isogenic control organoids, AD organoids with PSEN2N141I mutation recapitulated an AD-like pathology at the molecular, cellular, and network level, such as a higher Aβ42/Aβ40 ratio and enhanced neuronal hyperactivity. Altogether suggests these isogenic organoids as a promising tool for the pathological study of AD. |
| Cerebral organoids whole brain | AD | [54] | An episomal plasmid vector derived from EBV based simple and versatile genetic engineering was employed to efficiently generate organoids harboring a normal tau protein with fluorescent tag vs. a mutant genetic form (P301S) of tau that leads to fronto-temporal dementia. The harbored plasmid did not affect differentiation, and the isogenic organoid lines were stable for more than 30 passages expressing either normal or mutant form. The cerebral organoids manifested hyperphosphorylation of the tau protein, a pathologically relevant phenotype, contributing to disease modeling, personalized medicine and potentially translating to clinical therapeutics. |
| Cerebral organoids whole brain | AD | [55] | The enhanced spontaneous action potentials, slow oscillatory events (~1 Hz), and hypersynchronous network activity were detected in the AD neuronal organoids. The dual-allosteric NMDAR antagonist NitroSynapsin, revoked the hyperactivity, but the FDA-approved drug did not, suggesting the AD organoid models could be efficient tool for drug screening and modeling of the related synaptic damage in AD. |
| Cortical organoids cortex | AD | [51] | Time and spatial patterns of tau expression at a molecular level was compared during brain development using the iPSC-derived cortical organoids and developing human brains. Neuronal maturation led to the dramatic elevation of tau mRNAs, while low expression levels were observed in SVZ radial glia and deep white matter intermediate progenitors.
This system could help further study on the pathophysiological mechanism of triggering and enhancing tau expression, simplifying the identification of therapeutic targets for tauopathy-based neurodevelopmental disorders. |
| Human midbrain-like organoids (hMLOs) | Early-onset PD | [66] | DNAJC6 mutation vs. CRISPR-Cas9 manifestation of key PD features, pathologic neurodevelopment defects, DNAJC6- mediated endocytosis defect, impairment of the WNT-LMX1A signal during the mDA neuron development reduced LMX1A expression during development, generation of vulnerable mDA neurons |
| Midbrain organoids | PD | [57] | The first organoid model for an idiopathic form of PD and healthy volunteers were generated by the Sendai viral vector mediated transduction. The mature organoids manifested statistical differences in the expression levels of neuronal early and late markers between organoids from PD patient and healthy volunteer. Altogether suggests that PD human organoids could be potentially suitable for modeling PD and cellular interactions within the human brain. |
| Midbrain organoids | PD | [63] | Isogenic 3D midbrain organoids with or without a PD-associated LRRK2 G2019S mutation recapitulate the pathological hallmarks observed in patients with LRRK2-associated PD. The protein-protein interaction network in mutant organoids revealed that TXNIP, a thiol-oxidoreductase, is essential for development of LRRK2-associated Parkinson’s disease in a 3D environment.
Altogether suggests the potential of 3D organoid for modeling sporadic PD in advancing therapeutic discovery. |
| simBOs | PD | [58] | Simplified brain organoids (simBOs), composed of mature neurons and astroglial cells were rapidly generated in 2 weeks and have more homogeneous properties. The SimBOs facilitates the conversion of pNSCs to mature neuronal systems in the context of neurotransmitter release, synaptic vesicle formation, ion channels, calcium signaling, axonal guidance, extracellular matrix organization, and cell cycle.
The simBOs could easily be specified into midbrain-like simBOs by treatment with Shh and FGF8.
Midbrain-like simBOs from a PD patient (LRRK2G2019S)-derived pNSCs manifested disease-associated phenotypes in terms of increased LRRK2 activity, decreased dopaminergic neurons, and increased autophagy.
Treatment with the LRRK2 inhibitor, PFE-360, relieved the phenotype of Parkinson’s disease in midbrain-like simBOs. Taken together, these approaches could be applied to large-scale disease models and alternative drug-testing platforms. |
| Midbrain organoids | PD | [69] | The patient-based midbrain organoid model of PARK7-linked PD was created, and aberrant U1-dependent splicing was detected, causing a drastic reduction in DJ-1 protein and, consequently, mitochondrial dysfunction. Targeting defective exon skipping with genetically engineered U1-snRNA recovered DJ-1 protein expression in neuronal precursor cells and differentiated neurons.
Combinatorial treatment with the small-molecule compounds rectifier of aberrant splicing (RECTAS) and phenylbutyric acid, could restore DJ-1 protein and mitochondrial dysfunction in patient-derived fibroblasts as well as dopaminergic neuronal cell loss in mutant midbrain organoids. Therefore, this system could become an alternative strategy to restore cellular abnormalities in in vitro models of PD and provides a proof of concept for neuroprotection based on precision medicine strategies in PD. |
| Midbrain organoids | PD | [59] | The physicochemical properties of carbon fibers (CFs) scaffolds make CFs more advantageous over the conventionally applied PLGA scaffold in improving the efficiency of iPSC differentiation within organoids.
The organoid generated using CFs scaffolds were used for screening genes that expressed during the organoids differentiation at crucial stage of brain development. Correlation between PITX3, one of the essential factors for terminal differentiation and the survival of mDA neurons, and TH gene expression was detected. Thus, it is plausible to suggest that organoids containing mDA neurons formed on CFs could be suitable for investigation of the midbrain-associated NDD such as PD. |
| Midbrain organoids | PD | [60] | A fast and robust method to generate human midbrain organoids and incorporate microglia together with astrocytes into the organoids. These ratio-defined and three cell type-based organoids are suitable for the study on toxicology and pathophysiology of the CNS. |
| Midbrain organoids | PD | [70] | A midbrain PD organoid model was generated and applied to test and characterize the neurotoxic effect on dopaminergic neurons via a machine learning-based analytical method. This approach has been used for HCI cell profiling and toxicity evaluation in midbrain organoids treated with/without 6-OHDA, the neurotoxic compound. This platform could be employed for modeling PD and drug screening to identify the neurotoxic compounds |
| Midbrain organoids | PD | [61] | The homogeneous midbrain-like organoids (MOs) were generated with mature architecture of midbrain dopaminergic (mDA) neurons, other neuronal subtypes, and functional glial cells such as astrocytes and oligodendrocytes but no microglias. The MLOs are extremely sensitive to 1-methyl-4-phenyl-1,-2,3,6-tetrahydropyridine that conferred the mDA neuron-specific cell death. |
| Midbrain organoids | PD | [72] | The midbrain organoids generated by Renner et al., could recapitulate architecture, size, cellular composition, homogeneous morphology, aggregate-wide synchronized neural activity, and global gene expression. These midbrain organoids have been employed to create a scalable and HTS-compatible platform for drug screening and evaluation with criteria of HCI and RNA-seq at the single-cell level, generating the reproducible prediction of the drug effects on neurological disorders of PD. |
| Cerebral organoids | Schizophrenia | [21] | Cerebral organoids of four controls and three schizophrenia patients to model the first trimester of in utero brain development. It was found that progression of the cortical malformation was associated with aberrant FGFR1 signaling |
| Forebrain organoids | Schizophrenia | [22] | Schizophrenia patient derived forebrain organoids to model human brain development. It was found that disrupting DISC1/Ndel1 complex formation contributes to brain development of schizophrenia patient |
| Telencephalic organoids | ASD | [12] | The cerebral telencephalic organoids generated from affected families were utilized for modeling the idiopathic ASD for the first time with organoids from the unaffected family members as control. Molecularly, the altered gene expression network could contribute to the pathogenesis of ASD such as the enhanced expression of FOXG1, which leads to overproduction of GABAergic inhibitory neurons. Cellularly, the synaptic growth, cell cycle, and imbalance in GABAergic/glutamatergic neuron differentiation were significantly altered in the ASD organoids. |
| Cerebral organoids | ASD | [34] | Human cerebral organoids carrying the mutations of Rab39b, a small GTPase associated with X-linked macrocephaly, ASD, and intellectual disability, respectively. Cellularly, the proliferation of NPCs was promoted but the differentiation was impaired in the RAB39b mutant cerebral organoids, and ultimately the size of the organoids, whereby resembling the trait of ASD. These organoids have provided a cellular and molecular platform to study the pathophysiology of ASD and drug screening. |
| Cerebral organoids | ASD | [68] | Cortical organoids (mCOs) from CNTNAP2 KO mouse dysregulated generation of the GABAergic inhibitory neurons at cellular level and the transcriptional network involved in GABAergic neurogenesis at molecular level. And the dysregulations could be rescued by treatment with retigabine, an antiepileptic drug, indicating the potential Cntnap2 as a therapeutic target for clinical therapy of ASD |
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