Department of Biochemistry, National University of Singapore, Singapore.
Aging Cell. 2010 Oct;9(5):924-9. doi: 10.1111/j.1474-9726.2010.00597.x.
Sir2 ⁄ Sirt1 and its orthologues are known lifespan extension factors in several aging models from yeast to invertebrates. Sirt1 activation is also known to be beneficial and protective in both invertebrate and mammalian models of neurodegenerative disease. Sirt1’s lifespan extension effect, as well as the beneficial outcome of its activation in models of aging-associated diseases, is often attributed to its ability to instill a gene expression profile that is pro-survival and antiaging. A recent report from Nyström and colleagues showed that the yeast Sir2p affects the function of the polarisome in segregation and retrograde transport of damaged and aggregated proteins from the bud to the mother cell, thereby ensuring the generation of a 'rejuvenated' daughter cell. Interestingly, the role of Sir2p in this case involves deacetylation and activation of cytoplasmic chaperonin containing TCP-1 (CCT, or TriC), thereby enhancing actin folding and polymerization. In view of a previously documented role of CCT in modulating polyglutamine-containing protein aggregation and toxicity, we hypothesized that CCT deacetylation may also underlie Sirt1’s beneficial effects in several neurodegenerative diseases precipitated by toxic aggregates. Other than alterations in gene expression profile, another major way whereby Sirt1 activation may counter neural aging could be to promote neuronal survival via prevention of toxic aggregate formation through CCT.
Sir2 ⁄ Sirt1 及其同源物是几种衰老模型（从酵母到无脊椎动物）中已知的延长寿命的因素。Sirt1 的激活在神经退行性疾病的无脊椎动物和哺乳动物模型中也被证明是有益和保护性的。Sirt1 的延长寿命效应，以及其在与衰老相关疾病的模型中激活的有益结果，通常归因于它能够诱导一种促进生存和抗衰老的基因表达谱。Nyström 及其同事的最近一份报告显示，酵母 Sir2p 影响极体的功能，即从芽到母细胞中受损和聚集的蛋白质的分离和逆行运输，从而确保产生“更新”的子细胞。有趣的是，在这种情况下，Sir2p 的作用涉及细胞质伴侣蛋白含有 TCP-1（CCT，或 TriC）的去乙酰化和激活，从而增强肌动蛋白折叠和聚合。鉴于 CCT 在调节含有多聚谷氨酰胺的蛋白质聚集和毒性方面的先前记录的作用，我们假设 CCT 的去乙酰化也可能是 Sirt1 在几种由毒性聚集引发的神经退行性疾病中的有益作用的基础。除了基因表达谱的改变之外，Sirt1 激活可能通过 CCT 预防毒性聚集来促进神经元存活，从而对抗神经衰老的另一种主要方式。
