Microglia-specific overexpression of α-synuclein leads to severe dopaminergic neurodegeneration by phagocytic exhaustion and oxidative toxicity
Open accessAbstract
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.
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Misfolded proteins and protein aggregates, including tau, Aβ, α-synuclein, mutant huntingtin, TDP-43, SOD1, and FUS induce microglial activation and neuroinflammation.
“Numerous studies have reported that misfolded proteins and protein aggregates, including tau,136–139 Aβ,138,140 α-synuclein,141–144 mutant huntingtin,145 TDP-43,132,146 superoxide dismutase 1 (SOD1),147–149 and fused in sarcoma (FUS)150 induce microglial activation and neuroinflammation.”
From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [141]
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Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases
Loh, J. S., Mak, W. Q., Tan, L. K. S., Ng, C. X., Chan, H. H., Yeow, S. H., Foo, J. B., Ong, Y. S., How, C. W., & Khaw, K. Y. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-01743-1 · Cited by 1,193 · see citing works
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- Authors
- Bido, S., Muggeo, S., Massimino, L., Marzi, M. J., Giannelli, S. G., Melacini, E., Nannoni, M., Gambarè, D., Bellini, E., Ordazzo, G., Rossi, G., Maffezzini, C., Iannelli, A., Luoni, M., Bacigaluppi, M., Gregori, S., Nicassio, F., & Broccoli, V.
- Affiliations
- IRCCS Ospedale San Raffaele (IT)
- Italian Institute of Technology (IT)
- The San Raffaele Telethon Institute for Gene Therapy (IT)
- National Research Council (IT)
- Corresponding author
- Broccoli, Vania
- ORCID
- Venue
- Nature Communications
- Published
- 2021-10-29
- Volume
- 12
- Issue
- 1
- Pages
- 6237-6237
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC8556263
- OpenAlex
- W3208415654
- Cited by
- 190
- References
- 60
- Citations by year
- 2026: 30 · 2025: 50 · 2024: 41 · 2023: 39 · 2022: 29 · 2021: 1
- FWCI
- 11.01
- Type
- journal article
- Language
- en
- Update notices
- correction (2021-12-16)
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- BOA (University of Milano-Bicocca) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Ministero della Salute (PE-2016-02363550)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
- Keywords
- alpha-synuclein, microglia, Parkinson's disease, dopaminergic neuron loss, oxidative stress, nitrosative stress, microglial activation, interferon-gamma, peripheral immune cell infiltration, neuroinflammation, lentiviral overexpression, mouse model
- MeSH terms
- CX3C Chemokine Receptor 1, Animals, Encephalitis, Immunity, Innate, Male, Mice, Inbred C57BL, Mice, Transgenic, Nerve Degeneration, Nitric Oxide, Parkinson Disease, Phagocytosis, Substantia Nigra, Gene Expression, Reactive Oxygen Species, Microglia, Mice, alpha-Synuclein, Adaptive Immunity, Dopaminergic Neurons
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