Therapeutic Implications and Regulations of Protein Post-translational Modifications in Parkinsons Disease.

IF 3.6 4区医学 Q3 CELL BIOLOGY

Cellular and Molecular Neurobiology Pub Date : 2024-07-03 DOI:10.1007/s10571-024-01471-8

Twinkle Mishra, Shareen Singh, Thakur Gurjeet Singh

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Abstract

Parkinsons disease (PD) is a neurodegenerative disorder characterized by dopaminergic neuron loss and alpha-synuclein aggregation. This comprehensive review examines the intricate role of post-translational modifications (PTMs) in PD pathogenesis, focusing on DNA methylation, histone modifications, phosphorylation, SUMOylation, and ubiquitination. Targeted PTM modulation, particularly in key proteins like Parkin, DJ1, and PINK1, emerges as a promising therapeutic strategy for mitigating dopaminergic degeneration in PD. Dysregulated PTMs significantly contribute to the accumulation of toxic protein aggregates and dopaminergic neuronal dysfunction observed in PD. Targeting PTMs, including epigenetic strategies, addressing aberrant phosphorylation events, and modulating SUMOylation processes, provides potential avenues for intervention. The ubiquitin-proteasome system, governed by enzymes like Parkin and Nedd4, offers potential targets for clearing misfolded proteins and developing disease-modifying interventions. Compounds like ginkgolic acid, SUMO E1 enzyme inhibitors, and natural compounds like Indole-3-carbinol illustrate the feasibility of modulating PTMs for therapeutic purposes in PD. This review underscores the therapeutic potential of PTM-targeted interventions in modulating PD-related pathways, emphasizing the need for further research in this promising area of Parkinsons disease therapeutics.

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帕金森氏症中蛋白质翻译后修饰的治疗意义和调节。

帕金森病（PD）是一种神经退行性疾病，以多巴胺能神经元缺失和α-突触核蛋白聚集为特征。本综述探讨了翻译后修饰（PTM）在帕金森病发病机制中的复杂作用，重点关注 DNA 甲基化、组蛋白修饰、磷酸化、SUMOylation 和泛素化。靶向 PTM 调节，尤其是对 Parkin、DJ1 和 PINK1 等关键蛋白的调节，已成为缓解帕金森病多巴胺能变性的一种很有前景的治疗策略。PTM 失调在很大程度上导致了帕金森病中毒性蛋白质聚集的积累和多巴胺能神经元功能障碍。靶向 PTMs（包括表观遗传学策略）、处理异常磷酸化事件和调节 SUMOylation 过程为干预提供了潜在的途径。由Parkin和Nedd4等酶支配的泛素-蛋白酶体系统为清除折叠错误的蛋白质和开发改善疾病的干预措施提供了潜在的靶点。银杏酸、SUMO E1酶抑制剂等化合物以及吲哚-3-甲醇等天然化合物说明了调节PTMs以治疗帕金森病的可行性。本综述强调了以 PTM 为靶点的干预措施在调节帕金森病相关通路方面的治疗潜力，并强调了在这一前景广阔的帕金森病治疗领域开展进一步研究的必要性。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cellular and Molecular Neurobiology 生物-神经科学

CiteScore

7.70

自引率

0.00%

发文量

137

审稿时长

4-8 weeks

期刊介绍： Cellular and Molecular Neurobiology publishes original research concerned with the analysis of neuronal and brain function at the cellular and subcellular levels. The journal offers timely, peer-reviewed articles that describe anatomic, genetic, physiologic, pharmacologic, and biochemical approaches to the study of neuronal function and the analysis of elementary mechanisms. Studies are presented on isolated mammalian tissues and intact animals, with investigations aimed at the molecular mechanisms or neuronal responses at the level of single cells. Cellular and Molecular Neurobiology also presents studies of the effects of neurons on other organ systems, such as analysis of the electrical or biochemical response to neurotransmitters or neurohormones on smooth muscle or gland cells.