Pathogenic role of UPR (unfolded protein response) among hereditary leukoencephalopathy and neurodegenerative disorders after endoplasmic reticulum stress

Abstract

Endoplasmic reticulum (ER) is the protein-folding compartment. When the aggregation of unfolded or misfolded protein in the ER lumen excesses its folding capacity, unfolded protein response (UPR) and ER-associated protein degradation (ERAD) would be activated to eliminate the overload of nascent protein. However, the persistent ER stress would trigger apoptosis pathway and lead to cell death. There exist three pathways in the UPR process, which are mediated by three membrane receptors: PERK, ATF6 or IREl respectively. The first activated PERK would down regulates the protein synthesis through the phosphorylation of eukaryotic initiation factor (eIF) 2α (eIF2a) and activate the upstream open reading frame. ATF6 and IREl also make the contribution to UPR. Up to now, the most studied neurodegenerative diseases that related to ER stresses are Alzheimer's disease, Parkinson's disease, Vanishing White Matter disease, Pelizaeus-Merzbacher disease, Charcot-Marie-Tooth disease and CAG triplet repeat diseases (as Huntington's disease and Spinocerebellar ataxia).