Kim HJ, Raphael AR, LaDow ES, McGurk L, Weber RA, Trojanowski JQ, Lee VM, Finkbeiner S, Gitler AD, Bonini NM.
Therapeutic modulation of eIF2α phosphorylation rescues TDP-43 toxicity in amyotrophic lateral sclerosis disease models.
Nat Genet. 2014 Feb;46(2):152-60. Epub 2013 Dec 15
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This is a great article. The approach makes classic use of genetics to identify TDP-43 interactors, and in the process identifies a number of previously known and unknown players. The most interesting parts of the article for me are the experiments modulating eIF2α phosphorylation, which impacts on RNA translation and stress granule formation. They make the observation that genetic or chemical modulation of factors leading to inhibition of stress granule formation (e.g., knockdown or inhibition of PERK) mitigates the phenotype, while knockdown of GADD34, which increases stress granule formation, exacerbates the phenotype. This provides striking support for the hypothesis that excessive stress granule formation plays a large role in the pathophysiology of disease mediated by TDP-43.