SIRT2-knockdown rescues GARS-induced Charcot-Marie-Tooth neuropathy.
SIRT2-knockdown rescues GARS-induced Charcot-Marie-Tooth neuropathy.
复制标题
SIRT2 敲低可挽救 GARS 诱导的腓骨肌病
作者：
Zhao Y;Xie L;Shen C;Qi Q;Qin Y;Xing J;Zhou D;Qi Y;Yan Z;Lin X;Dai R;Lin J;Yu W
玛丽-Tooth病是最常见的遗传性周围神经病。甘氨酰-tRNA合成酶（加尔斯）基因的显性突变导致周围神经变性并导致CMT疾病2D型。加尔斯（GARSCMT 2D）突变在疾病发病机制中的潜在机制尚未完全了解。在这项研究中，我们报告了野生型加尔斯结合NAD+依赖性脱乙酰酶SIRT 2并抑制其脱乙酰活性，导致乙酰化的α微管蛋白，SIRT 2的主要底物。加尔斯的催化结构域与SIRT 2紧密相互作用，这是最CMT 2D突变定位。然而，加尔斯中的CMT 2D突变不能抑制SIRT 2去乙酰化，这导致乙酰化α微管蛋白减少。果蝇模型中SIRT 2的遗传减少挽救了加尔斯诱导的轴突CMT神经病变并延长了寿命。我们的研究结果证明了SIRT 2依赖性α微管蛋白脱乙酰化在突变型加尔斯诱导的神经病变中的致病作用，并为靶向SIRT 2作为遗传性轴突病的潜在治疗提供了新的视角。靶向SIRT 2作为乙酰化微管蛋白和CMT神经病变之间的关键节点的示意图。
Charcot‐Marie‐Tooth disease is the most common inherited peripheral neuropathy. Dominant mutations in the glycyl‐tRNA synthetase (GARS) gene cause peripheral nerve degeneration and lead to CMT disease type 2D. The underlying mechanisms of mutations in GARS (GARSCMT2D) in disease pathogenesis are not fully understood. In this study, we report that wild‐type GARS binds the NAD+‐dependent deacetylase SIRT2 and inhibits its deacetylation activity, resulting in the acetylated α‐tubulin, the major substrate of SIRT2. The catalytic domain of GARS tightly interacts with SIRT2, which is the most CMT2D mutation localization. However, CMT2D mutations in GARS cannot inhibit SIRT2 deacetylation, which leads to a decrease of acetylated α‐tubulin. Genetic reduction of SIRT2 in the Drosophila model rescues the GARS‐induced axonal CMT neuropathy and extends the life span. Our findings demonstrate the pathogenic role of SIRT2‐dependent α‐tubulin deacetylation in mutant GARS‐induced neuropathies and provide new perspectives for targeting SIRT2 as a potential therapy against hereditary axonopathies. Schematics of targeting SIRT2 as a critical node between acetylated tubulin and CMT neuropathy.
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影响因子：
64.8
作者：
He W;Bai G;Zhou H;Wei N;White NM;Lauer J;Liu H;Shi Y;Dumitru CD;Lettieri K;Shubayev V;Jordanova A;Guergueltcheva V;Griffin PR;Burgess RW;Pfaff SL;Yang XL
通讯作者：
Yang XL
影响因子：
4
作者：
Storkebaum, Erik
通讯作者：
Storkebaum, Erik
影响因子：
3.7
作者：
Bobrowska A;Donmez G;Weiss A;Guarente L;Bates G
通讯作者：
Bates G
影响因子：
9.8
作者：
Antonellis, A;Ellsworth, RE;Green, ED
通讯作者：
Green, ED
气管衍生的 dpp 控制果蝇成年中肠稳态。
影响因子：
11.8
作者：
Li, Zhouhua;Zhang, Yan;Lin, Xinhua
通讯作者：
Lin, Xinhua