Huntington’s disease (HD) is a fatal neurodegenerative disorder caused by an expanded polyglutamine repeat in huntingtin (Htt) protein. Current management strategies temporarily relieve disease symptoms, but fail to affect the underlying disease progression. We previously demonstrated that calorie restriction ameliorated HD pathogenesis and slowed disease progression in HD mice1. We now report that overexpression of SIRT1, a mediator of beneficial metabolic effects of calorie restriction, protects neurons against mutant Htt toxicity, whereas reduction of SIRT1 exacerbates mutant Htt toxicity. Overexpression of SIRT1 significantly improves motor function, reduces brain atrophy, and attenuates mutant Htt-mediated metabolic abnormalities in both fragment and full-length HD mouse models. Further mechanistic studies suggest that SIRT1 prevents mutant Htt-induced decline in BDNF levels and its receptor Trk-B signaling, and restores medium spiny neuronal DARPP32 levels in the striatum. SIRT1 deacetylase activity is required for SIRT1-mediated neuroprotection in HD models. Notably, we demonstrate that mutant Htt interacts with SIRT1 and inhibits SIRT1 deacetylase activity. Inhibition of SIRT1 deacetylase activity results in hyperacetylation of SIRT1 substrates such as FOXO3a thereby inhibiting its prosurvival function. Overexpression of SIRT1 counteracts mutant Htt-induced deacetylase deficit, enhances deacetylation of FOXO3a, and facilitates cell survival. These findings demonstrate a neuroprotective role of SIRT1 in mammalian HD models, indicate key mediators of this protection, and open new avenues for the development of neuroprotective strategies in HD.

No abstract

Background: Mitochondrial dysfunction is a key event mediating mutant Htt-induced neurotoxicity. Results: trans-(Ϫ)-⑀-Viniferin attenuates mutantHtt-induced SIRT3 depletion, activates AMPK, and preserves mitochondrial function. Conclusion: Increasing SIRT3 protects cells in HD.Significance: The result suggests a promising new target for development of HD therapeutics.