Journal
NATURE GENETICS
Volume 46, Issue 2, Pages 152-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.2853
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Funding
- Howard Hughes Medical Institute
- US National Institutes of Health [R01NS073660]
- NIH Director's New Innovator [DP2OD004417]
- US NIH grant [R01NS065317, AG10124, AG32953, AG17586, NS53488]
- Robert Packard Center for ALS and the Williams H. Adams Foundation
- Target ALS
- BrightFocus Alzheimer's disease research grant
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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. eIF2 alpha 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 eIF2 alpha 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.
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