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.