PDF(Pubmed)
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.
摘要：
帕金森病（PD）是一种神经退行性疾病，其特征是多巴胺能神经元丢失和α-突触核蛋白聚集。这篇全面的综述探讨了翻译后修饰（PTM）在PD发病机理中的复杂作用，专注于DNA甲基化，组蛋白修饰，磷酸化,SUMOylation,和泛素化。有针对性的PTM调制，特别是像Parkin这样的关键蛋白质，DJ1和PINK1是减轻PD中多巴胺能变性的有希望的治疗策略。在PD中观察到的异常调节的PTM显著促进了毒性蛋白聚集体的积累和多巴胺能神经元功能障碍。瞄准PTM，包括表观遗传策略，解决异常磷酸化事件，和调节SUMO化过程，提供了潜在的干预途径。泛素-蛋白酶体系统，由Parkin和Nedd4等酶控制，为清除错误折叠的蛋白质和开发疾病改善干预措施提供了潜在的目标。像银杏酸这样的化合物,SUMOE1酶抑制剂，和吲哚-3-甲醇等天然化合物说明了在PD中出于治疗目的调节PTM的可行性。这篇综述强调了PTM靶向干预在调节PD相关通路方面的治疗潜力，强调需要在这个有前途的帕金森病治疗领域进行进一步研究。
