去乙酰化酶1（SIRT1）是一種用來修復受損DNA的酶,，但8月《自然—神經(jīng)科學》上的一項報告發(fā)現(xiàn),，該酶還可以修復患有神經(jīng)退行性疾病諸如阿爾茲海默癥和肌萎縮側索硬化癥（又名“漸凍人”癥,，ALS）的小鼠體內的基因組不穩(wěn)定性,。
與身體中其他細胞不同,，成年哺乳動物大腦中的神經(jīng)元不會發(fā)生分裂。既然不能通過復制現(xiàn)有DNA來實現(xiàn)修復,，那么DNA受損以及導致的基因組不穩(wěn)定對神經(jīng)元來說是一件特別麻煩的事,。而且，DNA分子鏈的物理斷裂與衰老和神經(jīng)退行性疾病比如阿爾茲海默癥和ALS患病情況下的認知下降也存在著聯(lián)系,。
因為人們已經(jīng)知道去乙?；缚梢苑乐勾竽X細胞凋亡,，Li-Huei Tsai等人便研究了這種保護行為的分子機制,。他們發(fā)現(xiàn)，沒有SIRT1,，神經(jīng)元無法修復由有毒化學物質造成的DNA損傷,。此外,，他們還發(fā)現(xiàn)SIRT1的行為受到另一種酶的控制調節(jié)——這種酶負責將DNA包裹進行壓縮。該研究認為利用SIRT1激活藥物治療患有神經(jīng)退行性疾病和阿爾茲海默癥的小鼠的方法也能防止神經(jīng)元發(fā)生DNA損傷,。（生物谷 Bioon.com）
生物谷推薦的英文摘要
IRT1 collaborates with ATM and HDAC1 to maintain genomic stability in neurons
Matthew M Dobbin,1, 2, 3, 9 Ram Madabhushi,1, 2, 3, 9 Ling Pan,1, 2, 3 Yue Chen,4, 5 Dohoon Kim,6 Jun Gao,1, 2, 3, 8 Biafra Ahanonu,1, 2, 3 Ping-Chieh Pao,1, 2, 3 Yi Qiu,7 Yingming Zhao4, 5 & Li-Huei Tsai1, 2, 3
Nature Neuroscience doi:10.1038/nn.3460
Defects in DNA repair have been linked to cognitive decline with age and neurodegenerative disease, yet the mechanisms that protect neurons from genotoxic stress remain largely obscure. We sought to characterize the roles of the NAD+-dependent deacetylase SIRT1 in the neuronal response to DNA double-strand breaks (DSBs). We found that SIRT1 was rapidly recruited to DSBs in postmitotic neurons, where it showed a synergistic relationship with ataxia telangiectasia mutated (ATM). SIRT1 recruitment to breaks was ATM dependent; however, SIRT1 also stimulated ATM autophosphorylation and activity and stabilized ATM at DSB sites. After DSB induction, SIRT1 also bound the neuroprotective class I histone deacetylase HDAC1. We found that SIRT1 deacetylated HDAC1 and stimulated its enzymatic activity, which was necessary for DSB repair through the nonhomologous end-joining pathway. HDAC1 mutations that mimic a constitutively acetylated state rendered neurons more susceptible to DNA damage, whereas pharmacological SIRT1 activators that promoted HDAC1 deacetylation also reduced DNA damage in two mouse models of neurodegeneration. We propose that SIRT1 is an apical transducer of the DSB response and that SIRT1 activation offers an important therapeutic avenue in neurodegeneration.
