Journal Article

ER stress and the unfolded protein response in neurodegeneration

Saxena, Smita, Hetz, Claudio

2017

Overview

Key Points Many neurodegenerative diseases involve the accumulation of protein aggregates Endoplasmic reticulum (ER) stress triggers activation of the unfolded protein response (UPR), an adaptive reaction that restores cellular protein homeostasis, known as proteostasis Dysfunction of proteostasis is associated with abnormal levels of ER stress and is associated with neuronal degeneration in human post-mortem brain tissue Targeting the UPR can have distinct and even opposite effects on disease progression, depending on the disease context and the signalling branch that is analysed Gene therapy and pharmacological strategies to attenuate ER stress alleviates degeneration in various disease models Chronic ER stress not only results in neuronal loss, but also represses the synthesis of synaptic proteins, with implications for cognition and memory, and possibly autism spectrum disorder Accumulation of misfolded protein in neurons is a common feature of many neurodegenerative diseases. In this Review, Hetz and Saxena discuss the latest advances in our understanding about the mechanisms by which protein misfolding causes neurodegeneration, and look at novel insights into the role of cellular responses to protein misfolding in synaptic function and in inflammatory and mechanical injury in the nervous system. The clinical manifestation of neurodegenerative diseases is initiated by the selective alteration in the functionality of distinct neuronal populations. The pathology of many neurodegenerative diseases includes accumulation of misfolded proteins in the brain. In physiological conditions, the proteostasis network maintains normal protein folding, trafficking and degradation; alterations in this network — particularly disturbances to the function of endoplasmic reticulum (ER) — are thought to contribute to abnormal protein aggregation. ER stress triggers a signalling reaction known as the unfolded protein response (UPR), which induces adaptive programmes that improve protein folding and promote quality control mechanisms and degradative pathways or can activate apoptosis when damage is irreversible. In this Review, we discuss the latest advances in defining the functional contribution of ER stress to brain diseases, including novel evidence that relates the UPR to synaptic function, which has implications for cognition and memory. A complex concept is emerging wherein the consequences of ER stress can differ drastically depending on the disease context and the UPR signalling pathway that is altered. Strategies to target specific components of the UPR using small molecules and gene therapy are in development, and promise interesting avenues for future interventions to delay or stop neurodegeneration.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/80/470 / 692/617/375/365/1283 / 692/617/375/365/1917/1285 / 692/699/375/365/1718 / Analysis / Animals / Care and treatment / Endoplasmic reticulum / Endoplasmic Reticulum Stress / Humans / Inflammation - metabolism / Medicine & Public Health / Nerve Degeneration - metabolism / Neurodegeneration / Neurodegenerative diseases / Neurodegenerative Diseases - metabolism / Neurology / Neuronal Plasticity / Physiological aspects / Protein folding / Quality control / review-article / Signal Transduction / Unfolded Protein Response