HDAC6 is a therapeutic target in mutant GARS-induced Charcot-Marie-Tooth disease.
HDAC6 is a therapeutic target in mutant GARS-induced Charcot-Marie-Tooth disease.
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DOI：
10.1093/brain/awx375
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发表时间：
2018-03-01
期刊：
影响因子：
--
通讯作者：
Van Den Bosch L
中科院分区：
文献类型：
--
作者：
Benoy V;Van Helleputte L;Prior R;d'Ydewalle C;Haeck W;Geens N;Scheveneels W;Schevenels B;Cader MZ;Talbot K;Kozikowski AP;Vanden Berghe P;Van Damme P;Robberecht W;Van Den Bosch L
伴有显性轴突损失（CMT2）的腓骨肌痛患者表现出广泛的遗传异质性。Benoy等人证明了CMT2与组蛋白去乙酰化酶6 （HDAC6）之间的联系，后者控制α-微管蛋白的乙酰化，并提出药物抑制HDAC6对CMT2遗传变异具有治疗潜力。外周神经轴突需要一个组织良好的轴突微管网络进行有效的运输，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腓骨肌萎缩性侧索硬化症，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沙克-玛丽-图斯病治疗方法的发展。本研究的目的是探讨组蛋白去乙酰化酶6 （HDAC6）是否可以作为突变型glyyl - trna合成酶（GlyRS/GARS）诱导的周围神经病变的治疗靶点。C201R突变Gars小鼠模型的周围神经和背根神经节显示乙酰化α-微管蛋白水平降低。在初级背根神经节神经元中，突变型GlyRS影响神经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，这种相互作用被tubastatin A阻断，tubastatin A是HDAC6去乙酰化功能的选择性抑制剂。此外，HDAC6抑制恢复了表达glyrs的突变神经元的线粒体轴突运输。在突变体Gars小鼠中，全身递送一种特定的HDAC6抑制剂可增加周围神经α-微管蛋白乙酰化，部分恢复神经传导和运动行为。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是腓骨-腓骨-腓骨病的共同致病机制，它拓宽了选择性抑制HDAC6对其他遗传形式的腓骨-腓骨-腓骨病的治疗潜力。
Patients with Charcot-Marie-Tooth disease with predominant axonal loss (CMT2) show extensive genetic heterogeneity. Benoy et al. demonstrate a link between CMT2 and histone deacetylase 6 (HDAC6), which controls the acetylation of α-tubulin, and propose that pharmacological inhibition of HDAC6 has therapeutic potential in CMT2 genetic variants. 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.
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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：
4.5
作者：
Motley WW;Seburn KL;Nawaz MH;Miers KE;Cheng J;Antonellis A;Green ED;Talbot K;Yang XL;Fischbeck KH;Burgess RW
通讯作者：
Burgess RW
影响因子：
9.8
作者：
Antonellis, A;Ellsworth, RE;Green, ED
通讯作者：
Green, ED
DOI：
10.1136/jnnp-2013-305049
发表时间：
2013-11
期刊：
Journal of neurology, neurosurgery, and psychiatry
影响因子：
--
作者：
Gonzalez M;McLaughlin H;Houlden H;Guo M;Yo-Tsen L;Hadjivassilious M;Speziani F;Yang XL;Antonellis A;Reilly MM;Züchner S;Inherited Neuropathy Consortium
通讯作者：
Inherited Neuropathy Consortium
影响因子：
82.9
作者：
d'Ydewalle, Constantin;Krishnan, Jyothsna;Van Den Bosch, Ludo
通讯作者：
Van Den Bosch, Ludo