Microglia jointly degrade fibrillar alpha-synuclein cargo by distribution through tunneling nanotubes.
Microglia jointly degrade fibrillar alpha-synuclein cargo by distribution through tunneling nanotubes.
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小胶质细胞通过隧道纳米管进行物质分配，共同降解纤维状α - 突触核蛋白物质。
DOI：
10.1016/j.cell.2021.09.007
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发表时间：
2021-09-30
期刊：
影响因子：
64.5
通讯作者：
Heneka MT
中科院分区：
文献类型：
--
作者：
Scheiblich H;Dansokho C;Mercan D;Schmidt SV;Bousset L;Wischhof L;Eikens F;Odainic A;Spitzer J;Griep A;Schwartz S;Bano D;Latz E;Melki R;Heneka MT
小胶质细胞是CNS驻留的免疫细胞，其通过模式识别受体连接和炎症通路的激活对错误折叠的蛋白质进行反应。在这里，我们研究了小胶质细胞如何处理和科普α-突触核蛋白（α-syn）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-actin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幼稚小胶质细胞，在那里α-syn货物得到快速有效的降解。降低α-syn负荷可减弱小胶质细胞的炎症特征并改善其存活率。这种降解策略在携带LRRK 2 G2019 S突变的细胞中受到损害。我们使用器官型切片培养、双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。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。小胶质细胞迅速吞噬外源性α-突触核蛋白但对其降解犹豫不决α-突触核蛋白通过隧道纳米管在小胶质细胞之间转移健康的小胶质细胞向α-突触核蛋白超载的细胞提供线粒体分担α-突触核蛋白负荷减弱炎性小胶质细胞特征小胶质细胞形成F-肌动蛋白依赖的细胞间网络将α-突触核蛋白原纤维转移到邻近的小胶质细胞进行降解和清除。这一过程的损害，如帕金森病突变所见，导致炎症特征和细胞死亡增加。
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. Microglia rapidly engulf exogenous α-synuclein but hesitate in its degradation α-synuclein is transferred between microglia through tunneling nanotubes Healthy microglia donate mitochondria to α-synuclein overloaded cells Sharing the α-synuclein burden attenuated the inflammatory microglia profile Microglia form F-actin dependent intercellular networks to transfer α-synuclein fibrils to neighboring microglial cells for degradation and clearance. Impairment in this process, as seen with Parkinson’s disease mutations, leads to increased inflammatory profiles and cell death.
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