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

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

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

Author(s) -

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

Publication year - 2021

Publication title -

cell

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 26.304

H-Index - 776

eISSN - 1097-4172

pISSN - 0092-8674

DOI - 10.1016/j.cell.2021.09.007

Subject(s) - biology , microglia , alpha synuclein , microbiology and biotechnology , alpha (finance) , distribution (mathematics) , neuroscience , immunology , inflammation , parkinson's disease , medicine , mathematical analysis , disease , mathematics , pathology , construct validity , nursing , patient satisfaction

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.

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