Stress granules are dense aggregates that contain RNA and protein and appear in the cytosol under conditions of stress. A recent study, published online on December 15 in Nature Genetics by Nancy Bonini from the University of Pennsylvania and colleagues, may have found a key to reducing neuronal toxicity in ALS by modulating stress granules. In ALS patients carrying a mutated TAR DNA-binding protein 43 (TDP-43) gene TDP-43 accumulates in the cytoplasm rather than being localized to the nucleus and has a toxic effect on neurons. Previous work has demonstrated that genes that modulate stress granules also affect TDP-43 toxicity. In an attempt to reverse TDP-43 toxicity, the researchers targeted eIF2α, a translation initiation factor that is found in its phosphorylated form in stress granules. They used a small-molecule inhibitor of eIF2α phosphorylation developed by GlaxoSmithKline to try to inhibit stress granule accumulation in fruit fly and mammalian neurons. TDP-43-expressing flies treated with the inhibitor showed greater physical strength and better climbing ability than the untreated controls. The inhibitor also reduced the risk of cell death in these models. The findings could provide the groundwork for new ALS therapies that target stress granule accumulation.
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