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Novel HDAC6 Inhibitors Increase Tubulin Acetylation and Rescue Axonal Transport of Mitochondria in a Model of Charcot-Marie-Tooth Type 2F.
ACS Chemical Neuroscience ( IF 5 ) Pub Date : 2020-01-08 , DOI: 10.1021/acschemneuro.9b00338
Robert Adalbert 1, 2 , Akira Kaieda 3 , Christina Antoniou 1 , Andrea Loreto 1 , Xiuna Yang 1 , Jonathan Gilley 1 , Takashi Hoshino 3 , Keiko Uga 3 , Mahindra T Makhija 4 , Michael P Coleman 1, 5
Affiliation  

Disruption of axonal transport causes a number of rare, inherited axonopathies and is heavily implicated in a wide range of more common neurodegenerative disorders, many of them age-related. Acetylation of α-tubulin is one important regulatory mechanism, influencing microtubule stability and motor protein attachment. Of several strategies so far used to enhance axonal transport, increasing microtubule acetylation through inhibition of the deacetylase enzyme histone deacetylase 6 (HDAC6) has been one of the most effective. Several inhibitors have been developed and tested in animal and cellular models, but better drug candidates are still needed. Here we report the development and characterization of two highly potent HDAC6 inhibitors, which show low toxicity, promising pharmacokinetic properties, and enhance microtubule acetylation in the nanomolar range. We demonstrate their capacity to rescue axonal transport of mitochondria in a primary neuronal culture model of the inherited axonopathy Charcot-Marie-Tooth Type 2F, caused by a dominantly acting mutation in heat shock protein beta 1.

中文翻译:

新型 HDAC6 抑制剂可增加 2F 型腓骨肌萎缩症模型中微管蛋白乙酰化并拯救线粒体轴突运输。

轴突运输的破坏会导致许多罕见的遗传性轴突病,并与多种更常见的神经退行性疾病密切相关,其中许多与年龄有关。α-微管蛋白的乙酰化是一种重要的调节机制,影响微管稳定性和运动蛋白附着。迄今为止用于增强轴突运输的几种策略中,通过抑制脱乙酰酶组蛋白脱乙酰酶 6 (HDAC6) 来增加微管乙酰化是最有效的方法之一。几种抑制剂已经开发出来并在动物和细胞模型中进行了测试,但仍然需要更好的候选药物。在这里,我们报告了两种高效 HDAC6 抑制剂的开发和表征,它们显示出低毒性、有前景的药代动力学特性,并增强纳摩尔范围内的微管乙酰化。我们证明了它们在遗传性轴突病 2F 型(由热休克蛋白 β 1 的显性突变引起)的原代神经元培养模型中拯救线粒体轴突运输的能力。
更新日期:2020-01-08
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