HDAC6 inhibitors reverse axonal loss in a mouse model of mutant HSPB1-induced Charcot-Marie-Tooth disease
HDAC6 inhibitors reverse axonal loss in a mouse model of mutant HSPB1-induced Charcot-Marie-Tooth disease
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DOI：
10.1038/nm.2396
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发表时间：
2011-08-01
期刊：
影响因子：
82.9
通讯作者：
Van Den Bosch, Ludo
中科院分区：
文献类型：
--
作者：
d'Ydewalle, Constantin;Krishnan, Jyothsna;Van Den Bosch, Ludo
腓骨肌萎缩症 (CMT) 是周围神经系统最常见的遗传性疾病。 27 kDa 小热休克蛋白基因 (HSPB1) 的突变会导致轴突 CMT 或远端遗传性运动神经病 (远端 HMN)。我们开发并表征了仅在神经元中表达两种不同 HSPB1 突变（S135F 和 P182L）的转基因小鼠。这些小鼠表现出依赖于突变的 CMT 或远端 HMN 的所有特征。突变体 HSPB1 的表达降低了乙酰化 a-微管蛋白丰度并诱导严重的轴突运输缺陷。通过药物抑制组蛋白脱乙酰酶 6 (HDAC6) 诱导的 α-微管蛋白乙酰化增加，纠正了 HSPB1 突变引起的轴突运输缺陷，并挽救了有症状的突变 HSPB1 小鼠的 CMT 表型。我们的研究结果证明了α-微管蛋白脱乙酰化在突变型 HSPB1 诱导的神经病中的致病作用，并为使用 HDAC6 抑制剂作为遗传性轴突病的治疗策略提供了前景。
Charcot-Marie-Tooth disease (CMT) is the most common inherited disorder of the peripheral nervous system. Mutations in the 27-kDa small heat-shock protein gene (HSPB1) cause axonal CMT or distal hereditary motor neuropathy (distal HMN). We developed and characterized transgenic mice expressing two different HSPB1 mutations (S135F and P182L) in neurons only. These mice showed all features of CMT or distal HMN dependent on the mutation. Expression of mutant HSPB1 decreased acetylated a-tubulin abundance and induced severe axonal transport deficits. An increase of a-tubulin acetylation induced by pharmacological inhibition of histone deacetylase 6 (HDAC6) corrected the axonal transport defects caused by HSPB1 mutations and rescued the CMT phenotype of symptomatic mutant HSPB1 mice. Our findings demonstrate the pathogenic role of a-tubulin deacetylation in mutant HSPB1-induced neuropathies and offer perspectives for using HDAC6 inhibitors as a therapeutic strategy for hereditary axonopathies.