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Glutathione peroxidase activity is neuroprotective in models of Huntington's disease

Abstract

Huntington's disease is a fatal neurodegenerative disorder caused by a CAG repeat expansion encoding a polyglutamine tract in the huntingtin (Htt) protein1. Here we report a genome-wide overexpression suppressor screen in which we identified 317 ORFs that ameliorate the toxicity of a mutant Htt fragment in yeast and that have roles in diverse cellular processes, including mitochondrial import and copper metabolism. Two of these suppressors encode glutathione peroxidases (GPxs), which are conserved antioxidant enzymes that catalyze the reduction of hydrogen peroxide and lipid hydroperoxides2. Using genetic and pharmacological approaches in yeast, mammalian cells and Drosophila, we found that GPx activity robustly ameliorates Huntington's disease–relevant metrics and is more protective than other antioxidant approaches tested here. Notably, we found that GPx activity, unlike many antioxidant treatments, does not inhibit autophagy, which is an important mechanism for clearing mutant Htt. Because previous clinical trials have indicated that GPx mimetics are well tolerated in humans, this study may have important implications for treating Huntington's disease.

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Figure 1: Suppression of Htt103Q toxicity in yeast by ORF overexpression.
Figure 2: mGpx1 and ebselen improve Huntington's disease–relevant phenotypes in PC12 cells.
Figure 3: mGpx1 and ebselen ameliorate phenotypes in Huntington's disease flies.
Figure 4: Ebselen does not inhibit basal or induced autophagy.

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Acknowledgements

This study was supported by grants from the CHDI Foundation, Inc. and the Huntington's Disease Association to F.G. and C.P.K. J.C. was funded by a New Investigator Research Grant from the Medical Research Council to F.G. (G0700090), and M.C. was supported by a PhD studentship from the Biotechnology and Biological Sciences Research Council. We thank S. Macip for assistance with the FACS analysis. We thank E.D. Lynch for useful discussions related to this study and A. Winslow for advice on the autophagy protocol. We are grateful to L.M. Thompson (University of California, Irvine) for providing the PC12 cell lines and P. Taghert (Washington University, St. Louis), J.L. Marsh (University of California, Irvine), L.M. Thompson and R. Mockett (University of South Alabama) for providing transgenic fly lines. We thank M. Sherman and A. Meriin (Boston University School of Medicine, Boston) for providing yeast Htt constructs.

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F.G., C.P.K., R.P.M., M.C., N.B., C.B., S.C., J.C. and E.W.G. designed the experiments. R.P.M., M.C., N.B., C.B., S.C., J.C., D.D. and E.W.G. performed the experiments. F.G., R.P.M., C.P.K., M.C., C.B., S.C. and E.W.G. analyzed the data. R.P.M. and F.G. conducted the bioinformatics analysis. F.G., R.P.M. and C.P.K. wrote the manuscript.

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Correspondence to Flaviano Giorgini.

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Mason, R., Casu, M., Butler, N. et al. Glutathione peroxidase activity is neuroprotective in models of Huntington's disease. Nat Genet 45, 1249–1254 (2013). https://doi.org/10.1038/ng.2732

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