We report that Sir2 activation through increased sir-2.1 dosage or treatment with the sirtuin activator resveratrol specifically rescued early neuronal dysfunction phenotypes induced by mutant polyglutamines in transgenic Caenorhabditis elegans. These effects are dependent on daf-16 (Forkhead). Additionally, resveratrol rescued mutant polyglutamine–specific cell death in neuronal cells derived from HdhQ111 knock-in mice. We conclude that Sir2 activation may protect against mutant polyglutamines.
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This work was supported by the Institut National de la Santé et de la Recherche Médicale, the Cure Huntington's Disease Initiative of the High Q Foundation and the Association France Huntington. J.A.P. is supported by a postdoctoral fellowship from the Cure Huntington's Disease Initiative. M.A. is supported by a doctoral fellowship from the Institut National de la Santé et de la Recherche Médicale and the Région Ile-de-France. H.C. is supported by a doctoral fellowship from the Ministère de la Recherche.
The authors declare no competing financial interests.
Fisetin rescues mutant polyglutamine cytotoxicity. (PDF 1001 kb)
Increased sir-2.1 dosage protects axons from mutant polyglutamine-induced dystrophy. (PDF 865 kb)
Sirtuin inhibitors block resveratrol's rescue of mutant polyglutamine-induced cell death. (PDF 573 kb)
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Parker, J., Arango, M., Abderrahmane, S. et al. Resveratrol rescues mutant polyglutamine cytotoxicity in nematode and mammalian neurons. Nat Genet 37, 349–350 (2005). https://doi.org/10.1038/ng1534
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