摘要
组蛋白去乙酰化酶(HDACs)是表观遗传的酶,通过从组蛋白和非组蛋白底物中去除乙酰基部分,产生染色质的转录失活状态。 HDAC6调节分裂细胞以及有丝分裂后神经元中的若干生物途径,并且已经涉及神经变性的病理生理学。这些细胞中独特的细胞功能和存活依赖于HDAC6介导的过程,包括细胞内运输,分子伴侣介导的应激反应,抗氧化和蛋白质降解。因此,HDAC6作为治疗神经退行性疾病的有希望的治疗靶点的兴趣在过去十年中显着升高。考虑到这些严峻的事实,本文重点讨论HDAC6的结构组织。重要的是,我们讨论HDACs在认知和神经元死亡中的一般作用。此外,我们描述HDAC6在消除蛋白质聚集体,氧化应激和线粒体运输的独特参与。此外,文章严格详细说明HDAC6的活性受损如何在阿尔茨海默病(AD),帕金森病(PD),亨廷顿舞蹈病(HD),肌萎缩侧索硬化症(ALS)和脊髓性肌萎缩症(SMA)等神经退行性并发症中达到高潮。最后,我们提供了关于迷人的研究领域的清晰的观点,这些研究领域可能导致新型小分子的开发,从而增强治疗益处,以抵抗这些治疗性艰难的神经退行性疾病。
关键词: HDAC6,HDACi,AD,PD,AML,SMA,神经退行性疾病。
Current Medicinal Chemistry
Title:Small-molecule Modulation of HDAC6 Activity: The Propitious Therapeutic Strategy to Vanquish Neurodegenerative Disorders
Volume: 24 Issue: 37
关键词: HDAC6,HDACi,AD,PD,AML,SMA,神经退行性疾病。
摘要: Histone deacetylases (HDACs) are epigenetic enzymes creating the transcriptionally inactive state of chromatin by erasing acetyl moiety from histone and non-histone substrates. HDAC6 modulates several biological pathways in dividing cells as well as in post-mitotic neurons, and has been implicated in the pathophysiology of neurodegeneration. The distinct cellular functions and survival in these cells are reliant on HDAC6-mediated processes including intracellular trafficking, chaperone-mediated stress responses, anti-oxidation and protein degradation. Consequently, the interest in HDAC6 as a promising therapeutic target to tackle neurodegenerative disorders has escalated markedly over the last decade. Taking these grim facts into consideration, the current article focuses on structural organization of HDAC6. Importantly, we discuss the general role of HDACs in cognition and neuronal death. Further, we describe the unique involvement of HDAC6 in eliminating protein aggregates, oxidative stress and mitochondrial transport. Moreover, the article rigorously details how the impaired activity of HDAC6 culminates in neurodegenerative complications like Alzheimer disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). Lastly, we provide crystal clear view regarding the fascinating research areas which may lead to the development of novel small-molecules for enhanced therapeutic benefit against these therapeutically arduous neurodegenerative maladies.
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Cite this article as:
Small-molecule Modulation of HDAC6 Activity: The Propitious Therapeutic Strategy to Vanquish Neurodegenerative Disorders, Current Medicinal Chemistry 2017; 24 (37) . https://dx.doi.org/10.2174/0929867324666170209104030
DOI https://dx.doi.org/10.2174/0929867324666170209104030 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
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