Microglia are the CNS resident immune cells that react to misfolded proteins through pattern recognition receptor ligation and activation of inflammatory pathways. Here, we studied how microglia handle and cope with α-synuclein (α-syn) fibrils and their clearance. We found that microglia exposed to α-syn establish a cellular network through the formation of F-actin-dependent intercellular connections, which transfer α-syn from overloaded microglia to neighboring naive microglia where the α-syn cargo got rapidly and effectively degraded. Lowering the α-syn burden attenuated the inflammatory profile of microglia and improved their survival. This degradation strategy was compromised in cells carrying the LRRK2 G2019S mutation. We confirmed the intercellular transfer of α-syn assemblies in microglia using organotypic slice cultures, 2-photon microscopy, and neuropathology of patients. Together, these data identify a mechanism by which microglia create an “on-demand” functional network in order to improve pathogenic α-syn clearance.

小胶质细胞是中枢神经系统驻留免疫细胞，通过模式识别受体连接和激活炎症途径对错误折叠的蛋白质做出反应。在这里，我们研究了小胶质细胞如何处理和应对 α-突触核蛋白 (α-syn) 原纤维及其清除。我们发现暴露于α-syn的小胶质细胞通过形成依赖于F-肌动蛋白的细胞间连接建立了一个细胞网络，该连接将α-syn从超载的小胶质细胞转移到邻近的幼稚小胶质细胞，在那里α-syn货物被快速有效地降解。降低 α-syn 负荷可以减轻小胶质细胞的炎症并提高其存活率。这种降解策略在携带 LRRK2 G2019S 突变的细胞中受到损害。我们利用器官切片培养、2 光子显微镜和患者的神经病理学证实了小胶质细胞中 α-syn 组装体的细胞间转移。这些数据共同确定了小胶质细胞创建“按需”功能网络以改善致病性 α-syn 清除的机制。