Kumari Manisha, Bisht Krishna Singh, Ahuja Kriti, Motiani Rajender K, Maiti Tushar Kanti
Functional Proteomics Laboratory, Regional Centre for Biotechnology (RCB), NCR Biotech Science Cluster, Faridabad 121001, India.
Laboratory of Calciomics and Systemic Pathophysiology, Regional Centre for Biotechnology (RCB), NCR Biotech Science Cluster, Faridabad 121001, India.
ACS Chem Neurosci. 2024 Sep 25. doi: 10.1021/acschemneuro.4c00057.
α-Synuclein, a key player in Parkinson's disease and other synucleinopathies, possesses an inherently disordered structure that allows for versatile structural changes during aggregation. Microglia, the brain immune cells, respond differently to various α-synuclein strains, influencing their activation and release of harmful molecules, leading to neuronal death. Post-translational modifications, such as glycation in α-synuclein, add a layer of complexity to microglial activation. This study aimed to explore the impact of glycation on α-synuclein aggregation and microglial responses, which have not been studied before. Biophysical analyses revealed that glycated α-synuclein oligomers had distinct morphologies with a more negative and hydrophobic surface, preventing fibril formation and interfering with membrane interactions. Notably, there was increased cytosolic Ca dysregulation, redox stress, and mitochondrial instability compared to cells exposed to unmodified α-synuclein oligomers. Additionally, glycated α-synuclein oligomers exhibited impaired binding to Toll-like receptor 2, compromising downstream signaling. Surprisingly, these oligomers promoted TLR4 endocytosis and degradation. In our experiments with oligomers, glycated α-synuclein oligomers preferred NLRP3 inflammasome-mediated neuroinflammation, contributing differently from unmodified α-synuclein oligomers. In summary, this study unveils the mechanism underlying the effect of glycation on α-synuclein oligomers and highlights the conformation-specific microglial responses toward extracellular α-synuclein.
α-突触核蛋白是帕金森病和其他突触核蛋白病的关键因素，其结构内在无序，在聚集过程中可发生多种结构变化。小胶质细胞作为脑免疫细胞，对不同的α-突触核蛋白菌株有不同反应，影响其激活及有害分子的释放，导致神经元死亡。翻译后修饰，如α-突触核蛋白的糖基化，增加了小胶质细胞激活的复杂性。本研究旨在探讨糖基化对α-突触核蛋白聚集和小胶质细胞反应的影响，此前尚未对此进行过研究。生物物理分析表明，糖基化的α-突触核蛋白寡聚体具有独特的形态，表面更具负电性和疏水性，可阻止纤维形成并干扰膜相互作用。值得注意的是，与暴露于未修饰的α-突触核蛋白寡聚体的细胞相比，细胞内钙离子失调、氧化还原应激和线粒体不稳定性增加。此外，糖基化的α-突触核蛋白寡聚体与Toll样受体2的结合受损，影响下游信号传导。令人惊讶的是，这些寡聚体促进了TLR4的内吞作用和降解。在我们对寡聚体的实验中，糖基化的α-突触核蛋白寡聚体更倾向于通过NLRP3炎性小体介导神经炎症，其作用方式与未修饰的α-突触核蛋白寡聚体不同。总之，本研究揭示了糖基化对α-突触核蛋白寡聚体作用的机制，并突出了小胶质细胞对细胞外α-突触核蛋白的构象特异性反应。
