The class II histone deacetylases as therapeutic targets for Parkinson's disease.
The class II histone deacetylases as therapeutic targets for Parkinson's disease.
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DOI：
10.1042/ns20200001
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发表时间：
2020-06-01
影响因子：
--
通讯作者：
O'Keeffe, Gerard W
中科院分区：
文献类型：
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作者：
Mazzocchi, Martina;Collins, Louise M;O'Keeffe, Gerard W
帕金森病（PD）是一种进行性神经退行性疾病，其特征在于特定的运动障碍。PD的神经病理学特征包括中脑多巴胺能神经元的进行性变性，以及它们向纹状体的轴突投射的丧失。此外，存在α-突触核蛋白的细胞内聚集体的进行性积累和扩散。尽管多巴胺替代药物疗法可以在短期内治疗PD症状，但迫切需要在了解潜在疾病机制的基础上开发疾病改善疗法。其中一种机制是组蛋白乙酰化，这是一种常见的改变基因转录的表观遗传修饰。许多研究已经描述了PD患者脑中组蛋白乙酰化的改变。此外，α-突触核蛋白积累与组蛋白乙酰化的改变有关，并且正在研究旨在调节组蛋白乙酰化的药理学策略，作为PD疾病修饰的新方法。目前，这种策略主要集中在组蛋白脱乙酰酶（HDAC）酶的泛抑制。抑制特定的个体HDAC酶是一种更具针对性的策略，可以允许未来的临床转化。然而，在PD中应该靶向神经保护的最合适的HDAC类别仍然不清楚。最近的工作为II类HDAC在多巴胺能变性中的作用提供了新的线索。出于这个原因，在这里，我们描述了组蛋白乙酰化的调节，概述了PD脑中组蛋白乙酰化改变的证据，并重点关注II类HDAC的作用和II类HDAC抑制作为PD神经保护治疗方法的潜力。
Parkinson's disease (PD) is a progressive neurodegenerative disorder characterised by specific motor impairments. The neuropathological hallmarks of PD include progressive degeneration of midbrain dopaminergic neurons, and loss of their axonal projections to the striatum. Additionally, there is progressive accumulation and spread of intracellular aggregates of alpha-synuclein. Although dopamine-replacement pharmacotherapy can treat PD symptoms in the short-term, there is a critical need for the development of disease-modifying therapies based on an understanding of the underlying disease mechanisms. One such mechanism is histone acetylation, which is a common epigenetic modification that alters gene transcription. A number of studies have described alterations in histone acetylation in the brains of PD patients. Moreover, alpha-synuclein accumulation has been linked to alterations in histone acetylation and pharmacological strategies aimed at modulating histone acetylation are under investigation as novel approaches to disease modification in PD. Currently, such strategies are focused predominantly on pan-inhibition of histone deacetylase (HDAC) enzymes. Inhibition of specific individual HDAC enzymes is a more targeted strategy that may allow for future clinical translation. However, the most appropriate class of HDACs that should be targeted for neuroprotection in PD is still unclear. Recent work has shed new light on the role of class-II HDACs in dopaminergic degeneration. For this reason, here we describe the regulation of histone acetylation, outline the evidence for alterations in histone acetylation in the PD brain, and focus on the roles of class II HDACs and the potential of class-II HDAC inhibition as a therapeutic approach for neuroprotection in PD.