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Status |
Public on Sep 13, 2021 |
Title |
Microglia-specific overexpression of alpha-Synuclein leads to severe dopaminergic neurodegeneration by phagocytic exhaustion and oxidative toxicity [single-cell RNA-Seq] |
Organism |
Mus musculus |
Experiment type |
Expression profiling by high throughput sequencing
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Summary |
Increasing evidence from recent findings in human samples and animal models support the involvement of inflammation in the development of Parkinson’s disease (PD). Nevertheless, it is currently unknown whether microglia activation could also be a primary event leading to neurodegeneration in PD. We have generated a new mouse model with strictly selective alpha-Synuclein (aSYN) accumulation in microglial cells by inducible gene expression through lentiviral transduction in the nigral tissue. Surprisingly, these mice develop progressive and restricted degeneration of dopaminergic (DA) neurons without any sign of aSYN endogenous aggregation. aSYN accumulating microglial cells exhibit a strong inflammatory status with production of pro-inflammatory cytokines and chemokines. Bulk and scRNA-sequencing of the immune cellular infiltrate identify a complex cellular composition with numerous peripheral populations of the innate and adaptive immune system with specific transcriptional signatures. Molecular profiling and functional assessment reveal that intoxicated microglia develop exhausted phagocytosis and high production of oxidative molecules creating a molecular feed-forward vicious cycle with IFNg secreting immune cells infiltrated in the brain parenchyma. In these animals, pharmacological inhibition of the oxidative and nitrosative molecule production is sufficient to attenuate neurodegeneration. These results suggest that aSYN accumulation in microglia exerts selective DA neuronal degeneration by promoting phagocytic exhaustion, excessive toxic environment and selective recruitment of peripheral immune cells.
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Overall design |
1x CTRL (infected with GFP), 1x SNCA3 (CX3-Cre infected with Synuclein-expressing vector)
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Contributor(s) |
Massimino L, Bido S, Broccoli V |
Citation(s) |
34716339 |
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Submission date |
Sep 04, 2020 |
Last update date |
Dec 02, 2021 |
Contact name |
Luca Massimino |
E-mail(s) |
admin@lucamassimino.com
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Phone |
+393389039500
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Organization name |
Ospedale San Raffaele
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Department |
Gastroenterology
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Street address |
Via Olgettina, 58
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City |
Milano |
State/province |
MI |
ZIP/Postal code |
20100 |
Country |
Italy |
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Platforms (1) |
GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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Samples (2) |
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This SubSeries is part of SuperSeries: |
GSE157536 |
Microglia-specific overexpression of alpha-Synuclein leads to severe dopaminergic neurodegeneration by phagocytic exhaustion and oxidative toxicity |
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Relations |
BioProject |
PRJNA661582 |
SRA |
SRP280165 |