Unfolded proteins and endoplasmic reticulum stress in neurodegenerative disorders

Abstract

Introduction • ER stress and the UPR - The IRE1 axis: non-conventional splicing of XBP1 mRNA - The PERK axis: attenuation of translation - The ATF6 axis: regulated proteolytic activation • ER stress-induced apoptosis • ER stress and autophagy • The UPR and neurodegenerative disease - Alzheimer's disease - Parkinson's disease - Amyotrophic lateral sclerosis - Prion diseases • Future perspectives The stimuli for neuronal cell death in neurodegenerative disorders are multi-factorial and may include genetic predisposition, environmental factors, cellular stressors such as oxidative stress and free radical production, bioenergy failure, glutamate-induced excitotoxicity, neuroinflammation, disruption of Ca 2+-regulating systems, mitochondrial dysfunction and misfolded protein accumulation. Cellular stress disrupts functioning of the endoplasmic reticulum (ER), a critical organelle for protein quality control, leading to induction of the unfolded protein response (UPR). ER stress may contribute to neurodegeneration in a range of neurodegenerative disorders. This review summarizes the molecular events occurring during ER stress and the unfolded protein response and it specifically evaluates the evidence suggesting the ER stress response plays a role in neurodegenerative disorders. © 2011 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.