Soledad Matus, Fernanda Lisbona, Mauricio Torres, Cristian Leon, Peter Thielen and Claudio Hetz Pages 157 - 172 ( 16 )
The unfolded protein response (UPR) is a conserved adaptive reaction that increases cell survival under conditions of endoplasmic reticulum (ER) stress. The UPR controls diverse processes such as protein folding, secretion, ER biogenesis, protein quality control and macroautophagy. Occurrence of chronic ER stress has been extensively described in neurodegenerative conditions linked to protein misfolding and aggregation, including Amyotrophic lateral sclerosis, Prion-related disorders, and conditions such as Parkinsons, Huntingtons, and Alzheimers disease. Strong correlations are observed between disease progression, accumulation of protein aggregates, and induction of the UPR in animal and in vitro models of neurodegeneration. In addition, the first reports are available describing the engagement of ER stress responses in brain postmortem samples from human patients. Despite such findings, the role of the UPR in the central nervous system has not been addressed directly and its contribution to neurodegeneration remains speculative. Recently, however, pharmacological manipulation of ER stress and autophagy – a stress pathway modulated by the UPR – using chemical chaperones and autophagy activators has shown therapeutic benefits by attenuating protein misfolding in models of neurodegenerative disease. The most recent evidence addressing the role of the UPR and ER stress in neurodegenerative disorders is reviewed here, along with therapeutic strategies to alleviate ER stress in a disease context.
endoplasmic reticulum, X-Box-binding protein 1, chaperone-mediated autophagy, apoptosis, Amyotrophic Lateral Sclerosis
Director Laboratory Cellular Stress and Biomedicine, Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, Faculty of Medicine, The FONDAP Center for Molecular Studies of the Cell, University of Chile,Independencia 1027, P.O. Box 70086, Santiago, Chile.