麻省总医院的研究团队近日在《自然-医学》（Nature Medicine）杂志发表论文称，提高关键调节酶在大脑中的表达水平，可延缓亨廷顿病（HD）及其他神经退行性疾病脑细胞的破坏，从而起到治疗疾病的目的。
亨廷顿病、帕金森病、阿尔茨海默病等神经退行性疾病有各自不同的使动因素，但其病变类型却大致相同，如非正常蛋白质的积聚，神经细胞破坏等。
HD是一种遗传性疾病，其基本病变是编码亨廷顿蛋白的基因发生突变，不正常蛋白质在大脑中积聚，导致脑细胞破坏。其起始症状多出现在中年时期，10至30年后症状加重，最后因多种并发症而导致患者死亡。
Sirt1是一种重要的蛋白质活性调节酶，在调节能量代谢、炎症反应、应激耐受等方面发挥重要作用。最近有研究证实Sirt1具有对抗数种神经退行性疾病的作用。
该研究小组以小鼠为试验对象。通过建立小鼠HD模型，证实敲除Sirt1基因可加速HD样病变的进展；相反，Sirt1过表达的小鼠生存期较长，且神经变性及HD样病变较敲除小鼠显着减缓。细胞实验还证实Sirt1过表达可直接保护亨廷顿病小鼠的神经细胞。
研究者还发现了Sirt1的一个活性靶点--TORC1，该蛋白质负责调节数种重要神经元基因，而已知的亨廷顿突变可干扰Sirt1与TORC1的相互作用，从而降低受TORC1调节的基因的表达。
作者称，靶向Sirt1的药物或可为HD的治疗提供新的思路，甚至为大多数神经退行性疾病患者带来希望。（生物谷bioon.com）
doi:10.1016/10.1038/nm.2559
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Sirt1 mediates neuroprotection from mutant huntingtin by activation of the TORC1 and CREB transcriptional pathway
Sirt1 mediates neuroprotection from mutant huntingtin by activation of the TORC1 and CREB transcriptional pathway.
Sirt1, a NAD-dependent protein deacetylase, has emerged as a key regulator of mammalian transcription in response to cellular metabolic status and stress1. Here we show that Sirt1 has a neuroprotective role in models of Huntington's disease, an inherited neurodegenerative disorder caused by a glutamine repeat expansion in huntingtin protein (HTT)2. Brain-specific knockout of Sirt1 results in exacerbation of brain pathology in a mouse model of Huntington's disease, whereas overexpression of Sirt1 improves survival, neuropathology and the expression of brain-derived neurotrophic factor (BDNF) in Huntington's disease mice. We show that Sirt1 deacetylase activity directly targets neurons to mediate neuroprotection from mutant HTT. The neuroprotective effect of Sirt1 requires the presence of CREB-regulated transcription coactivator 1 (TORC1), a brain-specific modulator of CREB activity3. We show that under normal conditions, Sirt1 deacetylates and activates TORC1 by promoting its dephosphorylation and its interaction with CREB. We identified BDNF as a key target of Sirt1 and TORC1 transcriptional activity in both normal and Huntington's disease neurons. Mutant HTT interferes with the TORC1-CREB interaction to repress BDNF transcription, and Sirt1 rescues this defectin vitro and in vivo. These studies suggest a key role for Sirt1 in transcriptional networks in both the normal and Huntington's disease brain and offer an opportunity for therapeutic development.
