Novel HDAC6 Inhibitors Increase Tubulin Acetylation and Rescue Axonal Transport of Mitochondria in a Model of Charcot-Marie-Tooth Type 2F.
Novel HDAC6 Inhibitors Increase Tubulin Acetylation and Rescue Axonal Transport of Mitochondria in a Model of Charcot-Marie-Tooth Type 2F.
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DOI：
10.1021/acschemneuro.9b00338
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发表时间：
2020-02-05
影响因子：
5
通讯作者：
Coleman MP
中科院分区：
文献类型：
--
作者：
Adalbert R;Kaieda A;Antoniou C;Loreto A;Yang X;Gilley J;Hoshino T;Uga K;Makhija MT;Coleman MP
轴突运输的中断导致许多罕见的遗传性轴突病，并与广泛的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影响微管稳定性和运动蛋白附着的重要调节机制。在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HDAC 6来增加微管乙酰化是最有效的策略之一。已经开发了几种抑制剂，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HDAC 6抑制剂的开发和表征，它们显示出低毒性，有前途的药代动力学特性，并在纳摩尔范围内增强微管乙酰化。我们证明了他们的能力，以拯救轴突运输的线粒体在原代神经元培养模型的遗传性轴突病Charcot-Marie-Tooth 2F型，引起的显性作用突变热休克蛋白β 1。
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 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 characterisation 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.
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DOI：
10.1093/brain/awx370
发表时间：
2018-03-01
期刊：
Brain : a journal of neurology
影响因子：
--
作者：
Brenner D;Yilmaz R;Müller K;Grehl T;Petri S;Meyer T;Grosskreutz J;Weydt P;Ruf W;Neuwirth C;Weber M;Pinto S;Claeys KG;Schrank B;Jordan B;Knehr A;Günther K;Hübers A;Zeller D;Kubisch C;Jablonka S;Sendtner M;Klopstock T;de Carvalho M;Sperfeld A;Borck G;Volk AE;Dorst J;Weis J;Otto M;Schuster J;Del Tredici K;Braak H;Danzer KM;Freischmidt A;Meitinger T;Strom TM;Ludolph AC;Andersen PM;Weishaupt JH;German ALS network MND-NET
通讯作者：
German ALS network MND-NET
影响因子：
4.2
作者：
Adalbert R;Milde S;Durrant C;Ando K;Stygelbout V;Yilmaz Z;Gould S;Brion JP;Coleman MP
通讯作者：
Coleman MP
DOI：
10.1074/jbc.m109.082644
发表时间：
2010-04-23
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Almeida-Souza L;Goethals S;de Winter V;Dierick I;Gallardo R;Van Durme J;Irobi J;Gettemans J;Rousseau F;Schymkowitz J;Timmerman V;Janssens S
通讯作者：
Janssens S
DOI：
10.1073/pnas.0808084105
发表时间：
2008-10-14
影响因子：
11.1
作者：
Ittner, Lars M.;Fath, Thomas;Goetz, Juergen
通讯作者：
Goetz, Juergen
影响因子：
16.2
作者：
Alami NH;Smith RB;Carrasco MA;Williams LA;Winborn CS;Han SSW;Kiskinis E;Winborn B;Freibaum BD;Kanagaraj A;Clare AJ;Badders NM;Bilican B;Chaum E;Chandran S;Shaw CE;Eggan KC;Maniatis T;Taylor JP
通讯作者：
Taylor JP