Protein folding stress in neurodegenerative diseases: a glimpse into the ER

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Several neurodegenerative diseases share common neuropathology, primarily featuring the presence in the brain of abnormal protein inclusions containing specific misfolded proteins. Recent evidence indicates that alteration in organelle function is a common pathological feature of protein misfolding disorders, highlighting perturbations in the homeostasis of the endoplasmic reticulum (ER). Signs of ER stress have been detected in most experimental models of neurological disorders and more recently in brain samples from human patients with neurodegenerative disease. To cope with ER stress, cells activate an integrated signaling response termed the unfolded protein response (UPR), which aims to reestablish homeostasis in part through regulation of genes involved in protein folding, quality control and degradation pathways. Here we discuss the particular mechanisms currently proposed to be involved in the generation of protein folding stress in different neurodegenerative conditions and speculate about possible therapeutic interventions.

Introduction

Most neurodegenerative disorders share a common neuropathology associated with the accumulation of abnormal protein aggregates or inclusions in the brain containing specific misfolded proteins. These diseases include Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Huntington's disease (HD), prion-related disorders (PrDs), and many others [1, 2, 3, 4]. Abnormal protein aggregation in these diseases alters essential cellular functions, leading to neurological impairment and, in many cases neuronal loss. General perturbations to neuronal function could be related to synapse abnormalities, alteration in axonal transport, oxidative stress, proteasome inhibition, among other effects. Accumulating evidence in different neurodegenerative diseases indicates that subcellular organelle stress is a salient pathological event. Much attention has been given in the last ten years to the alterations of a particular subcellular organelle, the endoplasmic reticulum (ER), in the disease process. The ER is an essential compartment for the maturation and processing of proteins folded through the secretory pathway. In many neurodegenerative diseases the appearance of signs of ER stress is observed in the symptomatic and late disease stage. This article centers on recent findings illustrating the impact of protein folding stress at the ER in neurodegenerative conditions with distinct etiologies.

Section snippets

Cellular adaptation to protein folding stress: the UPR, ERAD and autophagy

One of the main functions of the ER is to initiate protein folding in the secretory pathway. A complex and dynamic network of protein chaperones, foldases, and co-factors are expressed at the ER lumen that catalyzes the folding and maturation of proteins, preventing their abnormal aggregation or misfolding. The ER also operates as a major calcium intracellular store and plays a vital role in the synthesis of lipids. Different alterations in ER homeostasis trigger the accumulation of abnormally

A function of the UPR in the physiology of the nervous system?

ER stress is observed in many physiological processes in secretory cells such as plasma B lymphocytes, salivary glands and pancreatic beta cells. In all these tissues the UPR plays an essential role in maintaining survival and functionality of secretory cells (reviewed in [13, 38, 39]). The high demand for efficient protein folding and secretion in those cells constitutes an endogenous and physiological source of stress associated with the presence of large amounts of abnormally folded proteins

ER stress in neurodegenerative conditions

Although signs of ER stress are observed in a variety of neurodegenerative diseases, the in vivo contribution of the pathway to the disease process has been established only in a few cases, and existing data are either correlative or arise from in vitro evidence. The functional significance of ER stress to neurodegeneration is complex and lends itself to three distinct but paradoxical interpretations. Activation of the UPR could promote neuronal protection by increasing the efficiency of

Concluding remarks

The exact role of the UPR in the central nervous system is not well defined. In this review we have summarized and discussed the available evidence supporting a strong association between accumulation of misfolded proteins and ER stress induction in several key neurodegenerative diseases. Although strong correlations exist between the misfolding and aggregation of an underlying protein and the presence of ER stress in neurodegenerative conditions, direct evidence to causally link the UPR and ER

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgments

This work was supported by FONDECYT (1100176), FONDAP (15010006), Millennium Nucleus (P07-048-F), CHDI Foundation Inc, Genzyme, Alzheimer's Association (NIRG-10-173294), M.J. Fox Foundation for Parkinson's Research, and ICGEB (CH); and ALSA-The Milton Safenowitz Post-Doctoral Fellowship for ALS Research 1829 and a fellowship from the Programa Atracción e Inserción de Capital Humano Avanzado CONICYT (79100007) (S.M.), and the National Institutes of Health (AI32412), a gift from the Mathers

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