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Therapeutic modulation of eIF2α phosphorylation rescues TDP-43 toxicity in amyotrophic lateral sclerosis disease models
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Therapeutic modulation of eIF2α phosphorylation rescues TDP-43 toxicity in amyotrophic lateral sclerosis disease models
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Journal Article
Therapeutic modulation of eIF2α phosphorylation rescues TDP-43 toxicity in amyotrophic lateral sclerosis disease models
2014
Overview
Nancy Bonini and colleagues performed a genome-wide yeast screen for modifiers of TDP-43 toxicity and identified genes in RNA metabolism, including several RNA-binding proteins with connections to stress granules. They determined that therapeutic modulation of stress granule–associated eIF2α phosphorylation rescues TDP-43 toxicity in amyotrophic lateral sclerosis disease models in flies and primary mammalian neurons.
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.
Publisher
Nature Publishing Group US,Nature Publishing Group
Subject
/ Adenine - analogs & derivatives
/ Amyotrophic lateral sclerosis
/ Amyotrophic Lateral Sclerosis - genetics
/ Analysis
/ Animal Genetics and Genomics
/ Animals
/ Ataxins
/ DNA-Binding Proteins - genetics
/ DNA-Binding Proteins - metabolism
/ Eukaryotic Initiation Factor-2 - metabolism
/ High-Throughput Screening Assays
/ Humans
/ Nerve Tissue Proteins - metabolism
/ Phosphorylation - drug effects
/ Poly(A)-Binding Proteins - metabolism
