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

Hannah Scheiblich (1, 2) , Cira Dansokho (1, 2) , Dilek Mercan (1, 2) , Susanne V. Schmidt (3) , Luc Bousset (4, 5) , Lena Wischhof (2) , Frederik Eikens (1, 2) , Alexandru Odainic (3) , Jasper Spitzer (3) , Angelika Griep (2) , Stephanie Schwartz (1) , Daniele Bano (2) , Eicke Latz (1, 2) , Ronald Melki (4, 5) , Michael T. Heneka (1, 2, 6)

1 University of Bonn
2 Dendrite Differenciation Group [DZNE - Bonn]
3 Institute of Innate Immunity, Bonn
4 CNRS - Centre National de la Recherche Scientifique
5 MIRCEN - Service MIRCEN
6 UMASS - University of Massachusetts Medical School [Worcester]

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.

Domains: Neurons and Cognition [q-bio.NC]

Hannah Scheiblich, Cira Dansokho, Dilek Mercan, Susanne V. Schmidt, Luc Bousset, et al.. Microglia jointly degrade fibrillar alpha-synuclein cargo by distribution through tunneling nanotubes. Cell, 2021, 184, pp.5089-5106. ⟨10.1016/j.cell.2021.09.007⟩. ⟨cea-03364079⟩