Stress signaling from the endoplasmic reticulum: a central player in the pathogenesis of amyotrophic lateral sclerosis

Walker, Adam K. and Atkin, Julie D. (2011) Stress signaling from the endoplasmic reticulum: a central player in the pathogenesis of amyotrophic lateral sclerosis. IUBMB Life, 63 9: 754-763. doi:10.1002/iub.520


Author Walker, Adam K.
Atkin, Julie D.
Title Stress signaling from the endoplasmic reticulum: a central player in the pathogenesis of amyotrophic lateral sclerosis
Journal name IUBMB Life   Check publisher's open access policy
ISSN 1521-6543
1521-6551
Publication date 2011-09-01
Sub-type Critical review of research, literature review, critical commentary
DOI 10.1002/iub.520
Open Access Status Not yet assessed
Volume 63
Issue 9
Start page 754
End page 763
Total pages 10
Place of publication Chichester, West Sussex, United Kingdom
Publisher Wiley-Blackwell Publishing
Language eng
Abstract Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by the misfolding and aggregation of distinct proteins in affected tissues, however, the pathogenic cause of disease remains unknown. Recent evidence indicates that endoplasmic reticulum (ER) stress plays a central role in ALS pathogenesis. ER stress activates the unfolded protein response (UPR), a homeostatic response to misfolded proteins. The UPR is initially protective by up‐regulation of specific ER stress‐regulated genes and inhibition of general protein translation. However, long‐term ER stress leads to cell death via apoptotic signaling, thus providing a link to neurodegeneration. Activation of the UPR is one of the earliest events in affected motor neurons of transgenic rodent models expressing ALS‐linked mutant superoxide dismutase 1 (SOD1). Recently, genetic manipulation of ER stress in several different SOD1 mouse models was shown to alter disease onset and progression, implicating an active role for the UPR in disease mechanisms. Furthermore, mutations to vesicle‐associated membrane protein‐associated protein B (VAPB), an ER transmembrane protein involved in ER stress regulation, also cause some cases of familial ALS. ER stress also occurs in spinal cord tissues of human sporadic ALS patients, and recent evidence suggests that perturbation of the ER could occur in ALS cases associated with TAR DNA binding protein 43 (TDP‐43), fused in sarcoma (FUS) and valosin containing protein (VCP). Together these findings implicate ER stress as a potential upstream mechanism involved in both familial and sporadic forms of ALS.
Keyword Amyotrophic lateral sclerosis
Apoptosis
Endoplasmic reticulum stress
Motor neuron
Neurodegeneration
Protein misfolding
Unfolded protein response
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Critical review of research, literature review, critical commentary
Collection: Queensland Brain Institute Publications
 
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