中国神经再生研究(英文版) ›› 2016, Vol. 11 ›› Issue (11): 1735-1738.doi: 10.4103/1673-5374.194803

• 综述:退行性病与再生 • 上一篇    下一篇

表观基因组可成为帕金森病的治疗标靶?

  

  • 出版日期:2016-11-30 发布日期:2016-11-30
  • 基金资助:
    作者实验室的研究得到爱尔兰研究委员会(R15897; SVH/AS/G'OK)和爱尔兰国立大学(R16189; SVH/AS/G'OK)的资助以及爱尔兰科学基金会(SFI)拨款号15/CDA/13498(G'OK)资助。

The Epigenome as a therapeutic target for Parkinson’s disease

Shane V. Hegarty*, #, Aideen M. Sullivan, Gerard W. O’Keeffe*, #   

  1. Department of Anatomy and Neuroscience, Biosciences Institute, University College Cork, Cork, Ireland
  • Online:2016-11-30 Published:2016-11-30
  • Contact: Shane V. Hegarty, Ph.D. or Gerard W. O’Kee?e, Ph.D., shane.hegarty@ucc.ie or g.okee?e@ucc.ie.
  • Supported by:
    Studies in the authors’ laboratories are supported by grants from the Irish Research Council (R15897; SVH/AS/G’OK) and the National University of Ireland (R16189; SVH/AS/G’OK) and a research group from Science Foundation Ireland (SFI) under the Grant Number 15/CDA/13498 (G’OK).

摘要:

来自爱尔兰科克大学Dr. Shane V. Hegarty认为,帕金森病是一种常见的、渐进神经退行性疾病,它的发病率随着年龄的增长而上升,终身患病率为1.5%。现在学科界越来越认识到表观遗传扰动因子对帕金森病患者的作用,而且这些因子也可能会对帕金森病理学造成影响。其中一个最广泛的表观遗传研究模型是DNA甲基化作用。科学家们在患者大脑和外周血白细胞中观察到了甲基化作用的独特模式(同时增加(亢奋)和降低(低沉)),也包括很多已报道的与帕金森病相关的基因。这些发现表示甲基化模型或许可以作为帕金森病后的生物标志物。 Dr. Shane V. Hegarty研究团队最新研究结果强调了药理靶标甲基化组对帕金森病的治疗潜力。例如,蛋氨酸给药(它整体提高了DNA甲基化作用水平)可以用来缓解左旋多巴诱发的运动障碍,而RG-108给药(降低整体DNA甲基化作用水平)加剧了左旋多巴诱发的运动障碍。这表明了DNA甲基化对与帕金森病有关的运动功能的重要性,而且提出了操纵甲基化组可作治疗帕金森病的可行治疗策略。

orcid:0000-0003-3456-0770 (Shane V. Hegarty),0000-0001-5149-0933 (Gerard W. O’Kee?e)

Abstract: Parkinson’s disease (PD) is a common, progressive neurodegenerative disease characterised by degeneration of nigrostriatal dopaminergic neurons, aggregation of α-synuclein and motor symptoms. Current dopamine-replacement strategies provide symptomatic relief, however their e?ectiveness wear o? over time and their prolonged use leads to disabling side-e?ects in PD patients. Tere is therefore a critical need to develop new drugs and drug targets to protect dopaminergic neurons and their axons from degeneration in PD. Over recent years, there has been robust evidence generated showing that epigenetic dysregulation occurs in PD patients, and that epigenetic modulation is a promising therapeutic approach for PD. Tis article frst discusses the present evidence implicating global, and dopaminergic neuron-specifc, alterations in the methylome in PD, and the therapeutic potential of pharmacologically targeting the methylome. It then focuses on another mechanism of epigenetic regulation, histone acetylation, and describes how the histone acetyltransferase (HAT) and histone deacetylase (HDAC) enzymes that mediate this process are attractive therapeutic targets for PD. It discusses the use of activators and/or inhibitors of HDACs and HATs in models of PD, and how these approaches for the selective modulation of histone acetylation elicit neuroprotective e?ects. Finally, it outlines the potential of employing small molecule epigenetic modulators as neuroprotective therapies for PD, and the future research that will be required to determine and realise this therapeutic potential.

Key words: Parkinson’s disease, epigenetics, methylation, acetylation, histone acetyltransferase, histone deacetylase, small molecules