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Department of Medicine, Division of Infectious Diseases and Immunology

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Cell Biology | Immunology and Infectious Disease


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 alpha-synuclein (alpha-syn) fibrils and their clearance. We found that microglia exposed to alpha-syn establish a cellular network through the formation of F-actin-dependent intercellular connections, which transfer alpha-syn from overloaded microglia to neighboring naive microglia where the alpha-syn cargo got rapidly and effectively degraded. Lowering the alpha-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 alpha-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 alpha-syn clearance.


LRRK2, alpha-synuclein, cell-to-cell transfer, clearance, degradation, microglia, synucleinopathies, tunneling nanotubes

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Copyright 2021 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (

DOI of Published Version



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. Microglia jointly degrade fibrillar alpha-synuclein cargo by distribution through tunneling nanotubes. Cell. 2021 Sep 30;184(20):5089-5106.e21. doi: 10.1016/j.cell.2021.09.007. Epub 2021 Sep 22. PMID: 34555357; PMCID: PMC8527836. Link to article on publisher's site

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Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.