Microglia jointly degrade fibrillar alpha-synuclein cargo by distribution through tunneling nanotubes.
Actins
/ metabolism
Aged
Aged, 80 and over
Animals
Apoptosis
Cell Membrane Structures
/ metabolism
Cytoskeleton
/ metabolism
Down-Regulation
Female
Humans
Inflammation
/ genetics
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
/ metabolism
Male
Mice, Inbred C57BL
Microglia
/ metabolism
Mitochondria
/ metabolism
Nanotubes
Protein Aggregates
Proteolysis
Reactive Oxygen Species
/ metabolism
Transcriptome
/ genetics
alpha-Synuclein
/ metabolism
LRRK2
alpha-synuclein
cell-to-cell transfer
clearance
degradation
microglia
synucleinopathies
tunneling nanotubes
Journal
Cell
ISSN: 1097-4172
Titre abrégé: Cell
Pays: United States
ID NLM: 0413066
Informations de publication
Date de publication:
30 09 2021
30 09 2021
Historique:
received:
20
07
2020
revised:
05
06
2021
accepted:
03
09
2021
pubmed:
24
9
2021
medline:
8
1
2022
entrez:
23
9
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 34555357
pii: S0092-8674(21)01054-0
doi: 10.1016/j.cell.2021.09.007
pmc: PMC8527836
pii:
doi:
Substances chimiques
Actins
0
Protein Aggregates
0
Reactive Oxygen Species
0
Tunneling Nanotubes
0
alpha-Synuclein
0
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
EC 2.7.11.1
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
5089-5106.e21Subventions
Organisme : NIA NIH HHS
ID : R01 AG059752
Pays : United States
Commentaires et corrections
Type : CommentIn
Type : CommentIn
Informations de copyright
Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests Michael T. Heneka serves as an advisory board member at IFM Therapeutics, Alector and Tiaki. He received honoraria for oral presentations from Novartis, Roche, and Biogen. The other authors declare that there is no conflict of interest with regard to the experimental part of this study.
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