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[211119 저널발표] Microglia jointly degrade fibrillar alpha-synuclein cargo by distribution through tunneling nanotubes

이동준 │ 2021-11-18

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Cell
Volume 184, Issue 20, 30 September 2021, Pages 5089-5106.e21
Journal home page for Cell

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

Highlights

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

Summary

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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