Neuroprotective role of Sirt1 in mammalian models of Huntington's disease through activation of multiple Sirt1 targets.
Neuroprotective role of Sirt1 in mammalian models of Huntington's disease through activation of multiple Sirt1 targets.
复制标题
DOI：
10.1038/nm.2558
复制
发表时间：
2011-12-18
期刊：
影响因子：
82.9
通讯作者：
Duan W
中科院分区：
文献类型：
--
作者：
Jiang M;Wang J;Fu J;Du L;Jeong H;West T;Xiang L;Peng Q;Hou Z;Cai H;Seredenina T;Arbez N;Zhu S;Sommers K;Qian J;Zhang J;Mori S;Yang XW;Tamashiro KL;Aja S;Moran TH;Luthi-Carter R;Martin B;Maudsley S;Mattson MP;Cichewicz RH;Ross CA;Holtzman DM;Krainc D;Duan W
亨廷顿病 (HD) 是一种致命的神经退行性疾病，由亨廷顿 (Htt) 蛋白中的聚谷氨酰胺重复序列扩展引起。目前的治疗策略暂时缓解疾病症状，但无法影响潜在的疾病进展。我们之前证明，热量限制可以改善 HD 小鼠的 HD 发病机制并减缓疾病进展。我们现在报道，SIRT1（热量限制的有益代谢作用的调节剂）的过度表达可以保护神经元免受突变体 Htt 毒性，而 SIRT1 的减少会加剧突变体 Htt 毒性。在片段和全长 HD 小鼠模型中，SIRT1 的过度表达可显着改善运动功能，减少脑萎缩，并减轻突变 Htt 介导的代谢异常。进一步的机制研究表明，SIRT1 可防止突变型 Htt 诱导的 BDNF 水平及其受体 Trk-B 信号传导下降，并恢复纹状体中中等棘神经元 DARPP32 水平。 SIRT1 脱乙酰酶活性是 HD 模型中 SIRT1 介导的神经保护所必需的。值得注意的是，我们证明突变体 Htt 与 SIRT1 相互作用并抑制 SIRT1 脱乙酰酶活性。抑制 SIRT1 脱乙酰酶活性会导致 SIRT1 底物（例如 FOXO3a）过度乙酰化，从而抑制其促生存功能。 SIRT1 的过度表达可以抵消突变体 Htt 诱导的脱乙酰酶缺陷，增强 FOXO3a 的脱乙酰化，并促进细胞存活。这些发现证明了 SIRT1 在哺乳动物 HD 模型中的神经保护作用，表明了这种保护的关键介质，并为 HD 神经保护策略的开发开辟了新途径。
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 mice. 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.