%0 Journal Article
%T Crosstalk between Endoplasmic Reticulum Stress and Protein Misfolding in Neurodegenerative Diseases
%A Cl¨¢udia M. F. Pereira
%J ISRN Cell Biology
%D 2013
%R 10.1155/2013/256404
%X Under physiological conditions, the endoplasmic reticulum (ER) is a central subcellular compartment for protein quality control in the secretory pathway that prevents protein misfolding and aggregation. Instrumental in protein quality control in the ER is the unfolded protein response (UPR), which is activated upon ER stress to reestablish homeostasis through a sophisticated transcriptionally and translationally regulated signaling network. However, this response can lead to apoptosis if the stress cannot be alleviated. The presence of abnormal protein aggregates containing specific misfolded proteins is recognized as the basis of numerous human conformational disorders, including neurodegenerative diseases. Here, I will highlight the overwhelming evidence that the presence of specific aberrant proteins in Alzheimer¡¯s disease (AD), Parkinson¡¯s disease (PD), Huntington¡¯s disease (HD), prion diseases, and Amyotrophic Lateral Sclerosis (ALS) is intimately associated with perturbations in the ER protein quality control machinery that become incompetent to restore protein homeostasis and shift adaptive programs toward the induction of apoptotic signaling to eliminate irreversibly damaged neurons. Increasing our understanding about the deadly crosstalk between ER dysfunction and protein misfolding in these neurodegenerative diseases may stimulate the development of novel therapeutic strategies able to support neuronal survival and ameliorate disease progression. 1. Endoplasmic Reticulum (ER) Stress and the Unfolded Protein Response (UPR) The endoplasmic reticulum (ER) is a crucial organelle involved in many functions in the cell, such as folding, assembly, and quality control of secretory and membrane proteins, disulfide bond formation, glycosylation, lipid biosynthesis, and Ca2+ storage and signaling [1]. When the protein-folding capacity in the ER is overwhelmed, unfolded or misfolded proteins accumulate in the ER lumen leading to ER stress [2]. To relieve stress and reestablish homeostasis, the ER activates intracellular signal transduction pathways, collectively termed the unfolded protein response (UPR), which reduces the influx of newly synthesized proteins into the ER through general translational arrest, induces the transcriptional upregulation of genes that enhance the ER protein-folding capacity and quality control, and also degrades proteins with aberrant conformation through the proteasome (ER-associated degradation, ERAD) and lysosome-mediated autophagy [3¨C6]. The canonical mammalian UPR pathway involves three specialized ER stress-sensing
%U http://www.hindawi.com/journals/isrn.cell.biology/2013/256404/