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ISRN Cell Biology
Volume 2013 (2013), Article ID 256404, 22 pages
Review Article

Crosstalk between Endoplasmic Reticulum Stress and Protein Misfolding in Neurodegenerative Diseases

Center for Neuroscience and Cell Biology (CNC) and Faculty of Medicine, University of Coimbra, Largo Marquês de Pombal, 3004-517 Coimbra, Portugal

Received 17 April 2013; Accepted 8 May 2013

Academic Editors: D. Arnoult, A. Colanzi, A. Hergovich, and E. Meacci

Copyright © 2013 Cláudia M. F. Pereira. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


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.