Microglia-specific overexpression of α-synuclein leads to severe dopaminergic neurodegeneration by phagocytic exhaustion and oxidative toxicity.
Adaptive Immunity
/ physiology
Animals
CX3C Chemokine Receptor 1
/ genetics
Dopaminergic Neurons
/ pathology
Encephalitis
/ metabolism
Gene Expression
Immunity, Innate
/ physiology
Male
Mice, Inbred C57BL
Mice, Transgenic
Microglia
/ drug effects
Nerve Degeneration
/ pathology
Nitric Oxide
/ metabolism
Parkinson Disease
/ pathology
Phagocytosis
/ physiology
Reactive Oxygen Species
/ metabolism
Substantia Nigra
/ metabolism
alpha-Synuclein
/ genetics
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
29 10 2021
29 10 2021
Historique:
received:
11
11
2020
accepted:
12
10
2021
entrez:
30
10
2021
pubmed:
31
10
2021
medline:
1
12
2021
Statut:
epublish
Résumé
Recent findings in human samples and animal models support the involvement of inflammation in the development of Parkinson's disease. Nevertheless, it is currently unknown whether microglial activation constitutes a primary event in neurodegeneration. We generated a new mouse model by lentiviral-mediated selective α-synuclein (αSYN) accumulation in microglial cells. Surprisingly, these mice developed progressive degeneration of dopaminergic (DA) neurons without endogenous αSYN aggregation. Transcriptomics and functional assessment revealed that αSYN-accumulating microglial cells developed a strong reactive state with phagocytic exhaustion and excessive production of oxidative and proinflammatory molecules. This inflammatory state created a molecular feed-forward vicious cycle between microglia and IFNγ-secreting immune cells infiltrating the brain parenchyma. Pharmacological inhibition of oxidative and nitrosative molecule production was sufficient to attenuate neurodegeneration. These results suggest that αSYN accumulation in microglia induces selective DA neuronal degeneration by promoting phagocytic exhaustion, an excessively toxic environment and the selective recruitment of peripheral immune cells.
Identifiants
pubmed: 34716339
doi: 10.1038/s41467-021-26519-x
pii: 10.1038/s41467-021-26519-x
pmc: PMC8556263
doi:
Substances chimiques
CX3C Chemokine Receptor 1
0
Cx3cr1 protein, mouse
0
Reactive Oxygen Species
0
SNCA protein, human
0
alpha-Synuclein
0
Nitric Oxide
31C4KY9ESH
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
6237Subventions
Organisme : Ministero della Salute (Ministry of Health, Italy)
ID : PE-2016-02363550
Commentaires et corrections
Type : ErratumIn
Informations de copyright
© 2021. The Author(s).
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