路易体和路易神经突的α-突触核蛋白(α-Syn)聚集已成为帕金森病(PD)的关键致病特征,路易体痴呆和多系统萎缩。各种因素,包括翻译后修饰(PTM),会影响α-Syn错折叠和聚集的倾向。PTM是在翻译期间或之后发生的蛋白质的生化修饰,并且通常由酶介导。PTM调节蛋白质的几个特征,包括它们的结构,活动,本地化,和稳定性。α-Syn经历各种翻译后修饰,包括磷酸化,泛素化,SUMOylation,乙酰化,糖化,O-GlcNAcylation,硝化,氧化,聚胺化,精氨酸化,和截断。蛋白质的不同PTM可以彼此物理地相互作用或一起工作以影响称为PTM串扰的过程中的特定生理或病理特征。近年来,用于PTM共现的检测技术的发展已经发现了以前未被理解的其串扰机制。这导致出现了支持α-SynPTM串扰与突触核蛋白病之间关联的证据。在这次审查中,我们提供了对α-SynPTM的全面评估,它们对错误折叠和致病性的影响,靶向它们的药理学手段,以及它们作为疾病生物标志物的潜力。我们还强调了这些PTM之间的串扰在α-Syn功能和聚集中的重要性。对这些PTMS及其串扰的复杂性的了解可以提高我们对突触核蛋白病发病机理的理解,并确定治疗潜力的新靶标。意义陈述α-突触核蛋白作为帕金森病和其他突触核蛋白病中的关键致病蛋白,使其成为疾病修饰的主要治疗目标。多种翻译后修饰发生在α-突触核蛋白的不同位点,并改变其生物物理和病理特性,一些相互作用,增加了这种蛋白质致病性的复杂性。这篇评论详细介绍了这些修改,它们对疾病的影响和潜在的治疗机会。
α-Synuclein (α-Syn) aggregation in Lewy bodies and Lewy neurites has emerged as a key pathogenetic feature in Parkinson\'s disease (PD), Dementia with Lewy Bodies and Multiple System Atrophy. Various factors, including post-translational modifications (PTMs), can influence the propensity of α-Syn to misfold and aggregate. PTMs are biochemical modifications of a protein that occur during or after translation and are typically mediated by enzymes. PTMs modulate several characteristics of proteins including their structure, activity, localization, and stability. α-Syn undergoes various post-translational modifications, including phosphorylation, ubiquitination, SUMOylation, acetylation, glycation, O-GlcNAcylation, nitration, oxidation, polyamination, arginylation, and truncation. Different PTMs of a protein can physically interact with one another or work together to influence a particular physiological or pathological feature in a process known as PTMs crosstalk. The development of detection techniques for the co-occurrence of PTMs in recent years has uncovered previously unappreciated mechanisms of their crosstalk. This has led to the emergence of evidence supporting an association between α-Syn PTMs crosstalk and synucleinopathies. In this review, we provide a comprehensive evaluation of α-Syn PTMs, their impact on misfolding and pathogenicity, the pharmacological means of targeting them, and their potential as biomarkers of disease. We also highlight the importance of the crosstalk between these PTMs in α-Syn function and aggregation. Insight into these PTMS and the complexities of their crosstalk can improve our understanding of the pathogenesis of synucleinopathies and identify novel targets of therapeutic potential. Significance Statement α-Synuclein as a key pathogenic protein in Parkinson\'s disease and other synucleinopathies, making it a leading therapeutic target for disease modification. Multiple post-translational modifications occur at various sites in α-Synuclein and alter its biophysical and pathological properties, some interacting with one another to add to the complexity of the pathogenicity of this protein. This review details these modifications, their implications in disease and potential therapeutic opportunities.