Crosstalk between Endoplasmic Reticulum Stress and Protein Misfolding in Neurodegenerative Diseases

Figure 3

ER stress triggered by misfolded proteins in several neurodegenerative diseases. Abnormal conformations of the proteins Aβ/tau, αSyn, HTT, PrP, and SOD1/VAPB/FTD-43/FUS are implicated in the pathogenesis of AD, PD, HD, prion diseases, and ALS, respectively. Alterations in the function of ER chaperones and UPR-related components, ERAD, ER/Golgi trafficking, and ER-to-mitochondria Ca²⁺ transfer have been suggested as underlying mechanisms of ER stress triggered by these disease-associated proteins. These proteins can accumulate and aggregate at the ER and their stable interaction with ER chaperones such as GRP78 and PDI may trap ER chaperones, altering protein folding with concomitant ER stress (1). In addition, these proteins can lead to the oxidative modification of the active site of PDIs by nitrosylation leading to their enzymatic inactivation. Furthermore, some of these proteins alter the activity of the UPR stress sensors (IRE1α, PERK, and ATF6) (2) as well as the activity/levels of downstream signaling mediators and transcription factors (3), including cleaved ATF6, ATF4, and spliced XBP1. As a result, genes implicated in autophagy and ERAD, antioxidant response, ER chaperones, and organelle’s biosynthesis are upregulated. Moreover, these proteins block the exit of vesicles from the ER and alter the trafficking between ER and Golgi of properly folded proteins (4). The cellular responses controlled by UPR transcription factors, including the modulation of autophagy-mediated degradation of protein aggregates (5), become compromised. Disease-related proteins can also interact with ERAD components (6), precluding the translocation of ERAD substrates from the ER to the cytosol, leading to the accumulation of abnormally folded proteins at the ER. Finally, Ca²⁺ released from the ER, mainly through the IP₃R, and its transfer to mitochondria can be impaired in the presence of disease-related proteins leading to mitochondrial Ca²⁺ overload and activation of apoptotic cell death pathways (7).