State Key Laboratory of Genetic Engineering, School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai, China.
School of Basic Medical Science, Southwest Medical University, Luzhou, China.
Aging Cell. 2021 Jun;20(6):e13391. doi: 10.1111/acel.13391. Epub 2021 May 30.
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 (GARS ) 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.
腓骨肌萎缩症是最常见的遗传性周围神经病。甘氨酰-tRNA 合成酶 (GARS) 基因的显性突变导致周围神经变性，导致 2D 型 CMT 疾病。GARS 突变（GARS）在疾病发病机制中的潜在机制尚未完全阐明。在这项研究中，我们报告野生型 GARS 结合 NAD 依赖性去乙酰化酶 SIRT2 并抑制其去乙酰化活性，导致 SIRT2 的主要底物乙酰化 α-微管蛋白。GARS 的催化结构域与 SIRT2 紧密相互作用，SIRT2 是最常见的 CMT2D 突变定位。然而，GARS 中的 CMT2D 突变不能抑制 SIRT2 的去乙酰化，导致乙酰化的 α-微管蛋白减少。在果蝇模型中遗传减少 SIRT2 可挽救 GARS 诱导的轴突 CMT 神经病并延长寿命。我们的发现表明 SIRT2 依赖性 α-微管蛋白去乙酰化在突变 GARS 诱导的神经病变中的致病作用，并为靶向 SIRT2 作为遗传性轴突病变的潜在治疗方法提供了新的视角。
