Amyloid-forming proteins such α-synuclein and tau, which are implicated in Alzheimer’s and Parkinson’s disease, can form different fibril structures or strains with distinct toxic properties, seeding activities and pathology. Understanding the determinants contributing to the formation of different amyloid features could open new avenues for developing disease-specific diagnostics and therapies. Here we report that O-GlcNAc modification of α-synuclein monomers results in the formation of amyloid fibril with distinct core structure, as revealed by cryogenic electron microscopy, and diminished seeding activity in seeding-based neuronal and rodent models of Parkinson’s disease. Although the mechanisms underpinning the seeding neutralization activity of the O-GlcNAc-modified fibrils remain unclear, our in vitro mechanistic studies indicate that heat shock proteins interactions with O-GlcNAc fibril inhibit their seeding activity, suggesting that the O-GlcNAc modification may alter the interactome of the α-synuclein fibrils in ways that lead to reduce seeding activity in vivo. Our results show that posttranslational modifications, such as O-GlcNAc modification, of α-synuclein are key determinants of α-synuclein amyloid strains and pathogenicity.

淀粉样蛋白形成蛋白，如 α-突触核蛋白和 tau 蛋白，与阿尔茨海默病和帕金森病有关，可以形成不同的原纤维结构或菌株，具有不同的毒性、播种活性和病理学。了解导致不同淀粉样蛋白特征形成的决定因素可以为开发特定疾病的诊断和治疗开辟新途径。在此，我们报告，α-突触核蛋白单体的 O-GlcNAc 修饰导致形成具有独特核心结构的淀粉样原纤维，正如低温电子显微镜所揭示的那样，并减少了基于接种的帕金森病神经元和啮齿动物模型中的接种活性。尽管 O-GlcNAc 修饰原纤维的播种中和活性的机制仍不清楚，但我们的体外机制研究表明，热休克蛋白与 O-GlcNAc 原纤维的相互作用抑制其播种活性，这表明 O-GlcNAc 修饰可能会改变α-突触核蛋白原纤维的相互作用组导致体内播种活性降低。我们的结果表明，α-突触核蛋白的翻译后修饰（例如 O-GlcNAc 修饰）是 α-突触核蛋白淀粉样蛋白菌株和致病性的关键决定因素。