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

Nature Genetics volume 46, pages 152–160 (2014)Cite this article

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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.

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Figure 1: A yeast plasmid overexpression screen highlights the role of stress granules in TDP-43 toxicity.
Figure 2: Genes that affect stress granule formation modulate TDP-43 toxicity.
Figure 3: The interaction between TDP-43 and ataxin-2 is mediated through the polyA-binding protein motif of ataxin-2.
Figure 4: PABP is required for TDP-43 toxicity.
Figure 5: PABPC1 is mislocalized in motor neurons from the tissue of humans with ALS.
Figure 6: PERK inhibitor treatment rescues TDP-43 toxicity in Drosophila and primary rat neurons.

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Acknowledgements

We thank X. Teng and Y. Zhu for technical assistance and W. Motley, A. Berson and other laboratory members for insightful comments. This work was funded by grants from the Howard Hughes Medical Institute (N.M.B.), grant R01NS073660 from the US National Institutes of Health (NIH; A.D.G. and N.M.B.), NIH Director's New Innovator Award DP2OD004417 (A.D.G.) and US NIH grant R01NS065317 (A.D.G.), the Robert Packard Center for ALS and the Williams H. Adams Foundation (S.F.), and US NIH grants AG10124, AG32953, AG17586 and NS53488 (J.Q.T. and V.M.-Y.L.). A.D.G. and S.F. are supported by a grant from Target ALS. A.R.R. is supported by a BrightFocus Alzheimer's disease research grant.

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  1. Hyung-Jun Kim

    Present address: Present address: Convergence Brain Research Department, Korea Brain Research Institute (KBRI), Daegu, South Korea.,

Authors and Affiliations

  1. Department of Biology, University of Pennsylvania, Philadelphia, Pennsylvania, USA

    Hyung-Jun Kim, Leeanne McGurk, Ross A Weber & Nancy M Bonini

  2. Department of Genetics, Stanford University School of Medicine, Stanford, California, USA

    Alya R Raphael & Aaron D Gitler

  3. Gladstone Institute of Neurological Disease, San Francisco, California, USA

    Eva S LaDow & Steven Finkbeiner

  4. Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.,

    John Q Trojanowski & Virginia M-Y Lee

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Contributions

H.-J.K., A.R.R., E.S.L., L.M. and A.D.G. conceived, designed and performed experiments, performed statistical analysis and analyzed data. R.A.W. performed experiments. J.Q.T. and V.M.-Y.L. contributed reagents and materials and provided experimental input. S.F., A.D.G. and N.M.B. conceived and designed experiments, analyzed data and supervised the research. H.-J.K. and N.M.B., with input from A.R.R. and A.D.G., wrote the manuscript.

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Correspondence to Nancy M Bonini.

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A.D.G. is an inventor on patents and patent applications for the gene hits from the yeast genetic screen that have been licensed to FoldRx.

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Kim, HJ., Raphael, A., LaDow, E. et al. Therapeutic modulation of eIF2α phosphorylation rescues TDP-43 toxicity in amyotrophic lateral sclerosis disease models. Nat Genet 46, 152–160 (2014). https://doi.org/10.1038/ng.2853

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