α-Synuclein misfolds into pathological forms that lead to various neurodegenerative diseases known collectively as α-synucleinopathies. In this Review, we provide a comprehensive overview of pivotal advances in α-synuclein research. We examine structural features and physiological functions of α-synuclein and summarize current insights into key post-translational modifications, such as nitration, phosphorylation, ubiquitination, sumoylation and truncation, considering their contributions to neurodegeneration. We also highlight the existence of disease-specific α-synuclein strains and their mechanisms of pathological spread, and discuss seed amplification assays and PET tracers as emerging diagnostic tools for detecting pathological α-synuclein in clinical settings. We also discuss α-synuclein aggregation and clearance mechanisms, and review cell-autonomous and non-cell-autonomous processes that contribute to neuronal death, including the roles of adaptive and innate immunity in α-synuclein-driven neurodegeneration. Finally, we highlight promising therapeutic approaches that target pathological α-synuclein and provide insights into emerging areas of research.

α-突触核蛋白错误折叠成病理形式，导致各种神经退行性疾病，统称为 α-突触核蛋白病。在本综述中，我们全面概述了 α-突触核蛋白研究的关键进展。我们研究了 α-突触核蛋白的结构特征和生理功能，并总结了当前对关键翻译后修饰的见解，例如硝化、磷酸化、泛素化、sumoylation 和截断，考虑到它们对神经退行性变的贡献。我们还强调了疾病特异性 α-突触核蛋白菌株的存在及其病理传播机制，并讨论了种子扩增测定和 PET 示踪剂作为临床环境中检测病理性 α-突触核蛋白的新兴诊断工具。我们还讨论了 α-突触核蛋白聚集和清除机制，并回顾了导致神经元死亡的细胞自主和非细胞自主过程，包括适应性免疫和先天免疫在 α-突触核蛋白驱动的神经变性中的作用。最后，我们重点介绍了针对病理性 α-突触核蛋白的有前途的治疗方法，并提供了对新兴研究领域的见解。