Journal article
ALS-associated TDP-43 induces endoplasmic reticulum stress, which drives cytoplasmic TDP-43 accumulation and stress granule formation
AK Walker, KY Soo, V Sundaramoorthy, S Parakh, Y Ma, MA Farg, RH Wallace, PJ Crouch, BJ Turner, MK Horne, JD Atkin
Plos One | Published : 2013
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-a, a key modulator of ER stress, potentiates ER ..
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Grants
Awarded by Australian Rotary Health
Funding Acknowledgements
This work was supported by the National Health and Medical Research Council of Australia (NHMRC, grants 454749, 1005651, 1006141, 1030513), www.nhmrc.gov.au, Amyotrophic Lateral Sclerosis Association, www.alsa.org, Bethlehem Griffiths Research Council, www.bethlehemgrf.com.au, a Henry H Roth Charitable Foundation Grant from the MND Research Institute of Australia, www.mndaust.asn.au/mndria, Australian Rotary Health, www.australianrotaryhealth.org.au, and the Brain Foundation, www.brainfoundation.org.au. AKW holds an NHMRC CJ Martin Biomedical Early Career Fellowship (1036835). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.