ALS-associated TDP-43 induces endoplasmic reticulum stress, which drives cytoplasmic TDP-43 accumulation and stress granule formation

Walker, Adam K., Soo, Kai Y., Sundaramoorthy, Vinod, Parakh, Sonam, Ma, Yi, Farg, Manal A., Wallace, Robyn H., Crouch, Peter J., Turner, Bradley J., Horne, Malcolm K. and Atkin, Julie D. (2013) ALS-associated TDP-43 induces endoplasmic reticulum stress, which drives cytoplasmic TDP-43 accumulation and stress granule formation. PLoS One, 8 11: e81170.1-e81170.12. doi:10.1371/journal.pone.0081170


Author Walker, Adam K.
Soo, Kai Y.
Sundaramoorthy, Vinod
Parakh, Sonam
Ma, Yi
Farg, Manal A.
Wallace, Robyn H.
Crouch, Peter J.
Turner, Bradley J.
Horne, Malcolm K.
Atkin, Julie D.
Title ALS-associated TDP-43 induces endoplasmic reticulum stress, which drives cytoplasmic TDP-43 accumulation and stress granule formation
Journal name PLoS One   Check publisher's open access policy
ISSN 1932-6203
Publication date 2013-11-01
Sub-type Article (original research)
DOI 10.1371/journal.pone.0081170
Open Access Status DOI
Volume 8
Issue 11
Start page e81170.1
End page e81170.12
Total pages 12
Place of publication San Francisco, CA, United States
Publisher Public Library of Science
Language eng
Abstract In amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration, TAR DNA binding protein 43 (TDP-43) accumulates in the cytoplasm of affected neurons and glia, where it associates with stress granules (SGs) and forms large inclusions. SGs form in response to cellular stress, including endoplasmic reticulum (ER) stress, which is induced in both familial and sporadic forms of ALS. Here we demonstrate that pharmacological induction of ER stress causes TDP-43 to accumulate in the cytoplasm, where TDP-43 also associates with SGs. Furthermore, treatment with salubrinal, an inhibitor of dephosphorylation of eukaryotic initiation factor 2-α, a key modulator of ER stress, potentiates ER stress-mediated SG formation. Inclusions of C-terminal fragment TDP-43, reminiscent of disease-pathology, form in close association with ER and Golgi compartments, further indicating the involvement of ER dysfunction in TDP-43-associated disease. Consistent with this notion, over-expression of ALS-linked mutant TDP-43, and to a lesser extent wildtype TDP-43, triggers several ER stress pathways in neuroblastoma cells. Similarly, we found an interaction between the ER chaperone protein disulphide isomerase and TDP-43 in transfected cell lysates and in the spinal cords of mutant A315T TDP-43 transgenic mice. This study provides evidence for ER stress as a pathogenic pathway in TDP-43-mediated disease.
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Queensland Brain Institute Publications
Official 2014 Collection
School of Chemistry and Molecular Biosciences
 
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