Peripheral nerve axons require a well-organized axonal microtubule network for efficient transport to ensure the constant crosstalk between soma and synapse. Mutations in more than 80 different genes cause Charcot-Marie-Tooth disease, which is the most common inherited disorder affecting peripheral nerves. This genetic heterogeneity has hampered the development of therapeutics for Charcot-Marie-Tooth disease. The aim of this study was to explore whether histone deacetylase 6 (HDAC6) can serve as a therapeutic target focusing on the mutant glycyl-tRNA synthetase (GlyRS/GARS)-induced peripheral neuropathy. Peripheral nerves and dorsal root ganglia from the C201R mutant Gars mouse model showed reduced acetylated α-tubulin levels. In primary dorsal root ganglion neurons, mutant GlyRS affected neurite length and disrupted normal mitochondrial transport. We demonstrated that GlyRS co-immunoprecipitated with HDAC6 and that this interaction was blocked by tubastatin A, a selective inhibitor of the deacetylating function of HDAC6. Moreover, HDAC6 inhibition restored mitochondrial axonal transport in mutant GlyRS-expressing neurons. Systemic delivery of a specific HDAC6 inhibitor increased α-tubulin acetylation in peripheral nerves and partially restored nerve conduction and motor behaviour in mutant Gars mice. Our study demonstrates that α-tubulin deacetylation and disrupted axonal transport may represent a common pathogenic mechanism underlying Charcot-Marie-Tooth disease and it broadens the therapeutic potential of selective HDAC6 inhibition to other genetic forms of axonal Charcot-Marie-Tooth disease.

中文翻译：

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HDAC6 是突变 GARS 诱导的 Charcot-Marie-Tooth 病的治疗靶点

周围神经轴突需要组织良好的轴突微管网络进行有效运输，以确保体细胞和突触之间的持续串扰。超过 80 种不同基因的突变导致 Charcot-Marie-Tooth 病，这是影响周围神经的最常见的遗传性疾病。这种遗传异质性阻碍了 Charcot-Marie-Tooth 病治疗方法的发展。本研究的目的是探索组蛋白去乙酰化酶 6 (HDAC6) 是否可以作为治疗靶点，专注于突变的甘氨酰-tRNA 合成酶 (GlyRS/ GARS ) 诱导的周围神经病变。C201R突变体Gars的外周神经和背根神经节小鼠模型显示乙酰化α-微管蛋白水平降低。在初级背根神经节神经元中，突变的 GlyRS 影响轴突长度并破坏正常的线粒体运输。我们证明 GlyRS 与 HDAC6 共免疫沉淀，并且这种相互作用被 HDAC6 去乙酰化功能的选择性抑制剂 tubastatin A 阻断。此外，HDAC6 抑制恢复了突变 GlyRS 表达神经元中的线粒体轴突运输。全身递送特定的 HDAC6 抑制剂可增加周围神经中的 α-微管蛋白乙酰化，并部分恢复突变Gars的神经传导和运动行为老鼠。我们的研究表明，α-微管蛋白去乙酰化和轴突运输中断可能代表 Charcot-Marie-Tooth 病的常见致病机制，并将选择性 HDAC6 抑制的治疗潜力扩大到其他遗传形式的轴突 Charcot-Marie-Tooth 病。