Therapeutic modulation of eIF2α phosphorylation rescues TDP-43 toxicity in amyotrophic lateral sclerosis disease models

Hyung Jun Kim, Alya R. Raphael, Eva S. Ladow, Leeanne Mcgurk, Ross A. Weber, John Q. Trojanowski, Virginia M. Y. Lee, Steven Finkbeiner, Aaron D. Gitler, Nancy M. Bonini (Lead / Corresponding author)

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192 Citations (Scopus)

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal, late-onset neurodegenerative disease primarily affecting motor neurons. A unifying feature of many proteins associated with ALS, including TDP-43 and ataxin-2, is that they localize to stress granules. Unexpectedly, we found that genes that modulate stress granules are strong modifiers of TDP-43 toxicity in Saccharomyces cerevisiae and Drosophila melanogaster. eIF2α phosphorylation is upregulated by TDP-43 toxicity in flies, and TDP-43 interacts with a central stress granule component, polyA-binding protein (PABP). In human ALS spinal cord neurons, PABP accumulates abnormally, suggesting that prolonged stress granule dysfunction may contribute to pathogenesis. We investigated the efficacy of a small molecule inhibitor of eIF2α phosphorylation in ALS models. Treatment with this inhibitor mitigated TDP-43 toxicity in flies and mammalian neurons. These findings indicate that the dysfunction induced by prolonged stress granule formation might contribute directly to ALS and that compounds that mitigate this process may represent a novel therapeutic approach.

Original languageEnglish
Pages (from-to)152-160
Number of pages9
JournalNature Genetics
Volume46
Issue number2
Early online date15 Dec 2013
DOIs
Publication statusPublished - Feb 2014

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    Kim, H. J., Raphael, A. R., Ladow, E. S., Mcgurk, L., Weber, R. A., Trojanowski, J. Q., Lee, V. M. Y., Finkbeiner, S., Gitler, A. D., & Bonini, N. M. (2014). Therapeutic modulation of eIF2α phosphorylation rescues TDP-43 toxicity in amyotrophic lateral sclerosis disease models. Nature Genetics, 46(2), 152-160. https://doi.org/10.1038/ng.2853