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.

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.

White matter abnormalities have been reported in premanifest Huntington's disease (HD) subjects before overt striatal neuronal loss, but whether the white matter changes represent a necessary step towards further pathology and the underlying mechanism of these changes remains unknown. Here, we characterized a novel knock-in mouse model that expresses mouse HD gene homolog (Hdh) with extended CAG repeat- HdhQ250, which was derived from the selective breeding of HdhQ150 mice. HdhQ250 mice manifest an accelerated and robust phenotype compared with its parent line. HdhQ250 mice exhibit progressive motor deficits, reduction in striatal and cortical volume, accumulation of mutant huntingtin aggregation, decreased levels of DARPP32 and BDNF and altered striatal metabolites. The abnormalities detected in this mouse model are reminiscent of several aspects of human HD. In addition, disturbed myelination was evident in postnatal Day 14 HdhQ250 mouse brain, including reduced levels of myelin regulatory factor and myelin basic protein, and decreased numbers of myelinated axons in the corpus callosum. Thinner myelin sheaths, indicated by increased G-ratio of myelin, were also detected in the corpus callosum of adult HdhQ250 mice. Moreover, proliferation of oligodendrocyte precursor cells is altered by mutant huntingtin both in vitro and in vivo. Our data indicate that this model is suitable for understanding comprehensive pathogenesis of HD in white matter and gray matter as well as developing therapeutics for HD.