麻省總醫(yī)院的研究團隊近日在《自然-醫(yī)學》（Nature Medicine）雜志發(fā)表論文稱，提高關(guān)鍵調(diào)節(jié)酶在大腦中的表達水平,，可延緩亨廷頓?。℉D）及其他神經(jīng)退行性疾病腦細胞的破壞,，從而起到治療疾病的目的。
亨廷頓病,、帕金森病,、阿爾茨海默病等神經(jīng)退行性疾病有各自不同的使動因素，但其病變類型卻大致相同,，如非正常蛋白質(zhì)的積聚,，神經(jīng)細胞破壞等。
HD是一種遺傳性疾病,，其基本病變是編碼亨廷頓蛋白的基因發(fā)生突變,，不正常蛋白質(zhì)在大腦中積聚，導致腦細胞破壞,。其起始癥狀多出現(xiàn)在中年時期,，10至30年后癥狀加重，最后因多種并發(fā)癥而導致患者死亡,。
Sirt1是一種重要的蛋白質(zhì)活性調(diào)節(jié)酶,，在調(diào)節(jié)能量代謝、炎癥反應,、應激耐受等方面發(fā)揮重要作用,。最近有研究證實Sirt1具有對抗數(shù)種神經(jīng)退行性疾病的作用。
該研究小組以小鼠為試驗對象,。通過建立小鼠HD模型,，證實敲除Sirt1基因可加速HD樣病變的進展；相反,，Sirt1過表達的小鼠生存期較長,，且神經(jīng)變性及HD樣病變較敲除小鼠顯著減緩。細胞實驗還證實Sirt1過表達可直接保護亨廷頓病小鼠的神經(jīng)細胞,。
研究者還發(fā)現(xiàn)了Sirt1的一個活性靶點--TORC1,，該蛋白質(zhì)負責調(diào)節(jié)數(shù)種重要神經(jīng)元基因，而已知的亨廷頓突變可干擾Sirt1與TORC1的相互作用,，從而降低受TORC1調(diào)節(jié)的基因的表達,。
作者稱，靶向Sirt1的藥物或可為HD的治療提供新的思路,，甚至為大多數(shù)神經(jīng)退行性疾病患者帶來希望,。（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.
