SIRT2 ablation has no effect on tubulin acetylation in brain, cholesterol biosynthesis or the progression of Huntington's disease phenotypes in vivo.
SIRT2 ablation has no effect on tubulin acetylation in brain, cholesterol biosynthesis or the progression of Huntington's disease phenotypes in vivo.
复制标题
DOI：
10.1371/journal.pone.0034805
复制
发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Bates G
中科院分区：
文献类型：
--
作者：
Bobrowska A;Donmez G;Weiss A;Guarente L;Bates G
亨廷顿病(HD)是一种毁灭性的神经退行性疾病，目前还没有治疗方法。HD的分子发病机制是复杂的，许多机制和细胞过程被认为是潜在的治疗干预部位。然而，在开始药物开发计划之前，治疗靶点能够在哺乳动物HD模型中得到验证是至关重要的。之前在无脊椎动物和细胞培养HD模型中的研究表明，抑制SIRT2可能会对疾病的进展产生有益的影响。SIRT2是一种依赖于NAD+的脱乙酰酶，被认为可以去乙酰化α-微管蛋白，组蛋白H4 K16，并调节胆固醇的生物生成-这是一种在HD患者和HD小鼠模型中调节失调的途径。我们利用SIRT2减少或消融的小鼠来进一步探索SIRT2的功能，并评估SIRT2缺失是否对HD的R6/2小鼠模型的疾病进展有有利影响。令人惊讶的是，我们发现SIRT2的减少或丢失对α-微管蛋白或H4K16的乙酰化或对野生型小鼠大脑中胆固醇的生物合成没有影响。同样，根据一系列生理和行为测试的评估，SIRT2的基因减少或消融对HD进展没有影响。此外，我们没有观察到聚集量或可溶性突变亨廷顿蛋白转运蛋白水平的变化。有趣的是，结构性遗传缺失和SIRT2的急性药物抑制都没有影响HD背景下胆固醇生物合成酶的表达。因此，我们得出结论，抑制SIRT2不会改变R6/2 HD小鼠模型的疾病进展，并且SIRT2抑制不应被优先作为HD的治疗选择。
Huntington's disease (HD) is a devastating neurodegenerative disorder for which there are no disease-modifying treatments. The molecular pathogenesis of HD is complex and many mechanisms and cellular processes have been proposed as potential sites of therapeutic intervention. However, prior to embarking on drug development initiatives, it is essential that therapeutic targets can be validated in mammalian models of HD. Previous studies in invertebrate and cell culture HD models have suggested that inhibition of SIRT2 could have beneficial consequences on disease progression. SIRT2 is a NAD+-dependent deacetylase that has been proposed to deacetylate α-tubulin, histone H4 K16 and to regulate cholesterol biogenesis – a pathway which is dysregulated in HD patients and HD mouse models. We have utilized mice in which SIRT2 has been reduced or ablated to further explore the function of SIRT2 and to assess whether SIRT2 loss has a beneficial impact on disease progression in the R6/2 mouse model of HD. Surprisingly we found that reduction or loss of SIRT2 had no effect on the acetylation of α-tubulin or H4K16 or on cholesterol biosynthesis in the brains of wild type mice. Equally, genetic reduction or ablation of SIRT2 had no effect on HD progression as assessed by a battery of physiological and behavioural tests. Furthermore, we observed no change in aggregate load or levels of soluble mutant huntingtin transprotein. Intriguingly, neither the constitutive genetic loss nor acute pharmacological inhibition of SIRT2 affected the expression of cholesterol biosynthesis enzymes in the context of HD. Therefore, we conclude that SIRT2 inhibition does not modify disease progression in the R6/2 mouse model of HD and SIRT2 inhibition should not be prioritised as a therapeutic option for HD.
登录
查看更多内容
影响因子：
29
作者：
Jing, Enxuan;Gesta, Stephane;Kahn, C. Ronald
通讯作者：
Kahn, C. Ronald
影响因子：
64.5
作者：
Graham, Rona K.;Deng, Yu;Hayden, Michael R.
通讯作者：
Hayden, Michael R.
影响因子：
30.8
作者：
ANDREW, SE;GOLDBERG, YP;HAYDEN, MR
通讯作者：
HAYDEN, MR
影响因子：
16.2
作者：
Crook ZR;Housman D
通讯作者：
Housman D
影响因子：
82.9
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
通讯作者：
Duan W