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科学家揭示小胶质细胞降解纤维状α-突触核蛋白的机制
作者:小柯机器人 发布时间:2021/9/24 13:59:51

德国波恩大学医学中心Michael T. Heneka团队发现,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。该研究于2021年9月22日发表于国际学术期刊《细胞》杂志。

研究人员探究了小胶质细胞如何处理和应对α-突触核蛋白(α-syn)原纤维以及如何将其清除。研究发现感知α-syn的小胶质细胞通过形成F-肌动蛋白依赖的细胞间连接建立细胞网络,将α-syn从过载的小胶质细胞转移到邻近的新生小胶质细胞,在那里α-syn被迅速有效地降解。降低α-syn负荷减弱了小胶质细胞的炎症反应并提高了其存活率。这种降解策略在携带LRRK2G2019S突变的细胞中受到损害。

研究人员使用器官切片培养、双光子显微镜和患者神经病理学证实了小胶质细胞中存在α-syn组件的细胞间转移。总之,这些数据揭示了小胶质细胞通过创建“按需”功能网络以清除致病性α-syn的机制。

据了解,小胶质细胞是CNS内的常驻免疫细胞,通过与模式识别受体结合和激活炎症通路对错误折叠的蛋白质作出反应。

附:英文原文

Title: Microglia jointly degrade fibrillar alpha-synuclein cargo by distribution through tunneling nanotubes

Author: Hannah Scheiblich, Cira Dansokho, Dilek Mercan, Susanne V. Schmidt, Luc Bousset, Lena Wischhof, Frederik Eikens, Alexandru Odainic, Jasper Spitzer, Angelika Griep, Stephanie Schwartz, Daniele Bano, Eicke Latz, Ronald Melki, Michael T. Heneka

Issue&Volume: 2021-09-22

Abstract: 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.

DOI: 10.1016/j.cell.2021.09.007

Source: https://www.cell.com/cell/fulltext/S0092-8674(21)01054-0

期刊信息
Cell:《细胞》,创刊于1974年。隶属于细胞出版社,最新IF:36.216
官方网址:https://www.cell.com/