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Microglia jointly degrade fibrillar alpha-synuclein cargo by distribution through tunneling nanotubes
Cell ( IF 64.5 ) Pub Date : 2021-09-22 , DOI: 10.1016/j.cell.2021.09.007
Hannah Scheiblich 1 , Cira Dansokho 1 , Dilek Mercan 1 , Susanne V Schmidt 2 , Luc Bousset 3 , Lena Wischhof 4 , Frederik Eikens 1 , Alexandru Odainic 2 , Jasper Spitzer 2 , Angelika Griep 4 , Stephanie Schwartz 5 , Daniele Bano 4 , Eicke Latz 6 , Ronald Melki 3 , Michael T Heneka 7
Affiliation  

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.



中文翻译:

小胶质细胞通过隧道纳米管分布共同降解纤维状α-突触核蛋白货物

小胶质细胞是 CNS 常驻免疫细胞,通过模式识别受体结扎和激活炎症通路对错误折叠的蛋白质作出反应。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 F-肌动蛋白依赖性细胞间连接来建立细胞网络,将 α-syn 从过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 货物迅速有效地降解。降低 α-syn 负荷减弱了小胶质细胞的炎症特征并提高了它们的存活率。这种降解策略在携带 LRRK2 G2019S 突变的细胞中受到损害。我们使用器官切片培养证实了小胶质细胞中 α-syn 组件的细胞间转移,2光子显微镜和患者的神经病理学。总之,这些数据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。

更新日期:2021-10-01
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