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Microglia-specific overexpression of α-synuclein leads to severe dopaminergic neurodegeneration by phagocytic exhaustion and oxidative toxicity

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-med...

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Autores principales: Bido, Simone, Muggeo, Sharon, Massimino, Luca, Marzi, Matteo Jacopo, Giannelli, Serena Gea, Melacini, Elena, Nannoni, Melania, Gambarè, Diana, Bellini, Edoardo, Ordazzo, Gabriele, Rossi, Greta, Maffezzini, Camilla, Iannelli, Angelo, Luoni, Mirko, Bacigaluppi, Marco, Gregori, Silvia, Nicassio, Francesco, Broccoli, Vania
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8556263/
https://www.ncbi.nlm.nih.gov/pubmed/34716339
http://dx.doi.org/10.1038/s41467-021-26519-x
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author Bido, Simone
Muggeo, Sharon
Massimino, Luca
Marzi, Matteo Jacopo
Giannelli, Serena Gea
Melacini, Elena
Nannoni, Melania
Gambarè, Diana
Bellini, Edoardo
Ordazzo, Gabriele
Rossi, Greta
Maffezzini, Camilla
Iannelli, Angelo
Luoni, Mirko
Bacigaluppi, Marco
Gregori, Silvia
Nicassio, Francesco
Broccoli, Vania
author_facet Bido, Simone
Muggeo, Sharon
Massimino, Luca
Marzi, Matteo Jacopo
Giannelli, Serena Gea
Melacini, Elena
Nannoni, Melania
Gambarè, Diana
Bellini, Edoardo
Ordazzo, Gabriele
Rossi, Greta
Maffezzini, Camilla
Iannelli, Angelo
Luoni, Mirko
Bacigaluppi, Marco
Gregori, Silvia
Nicassio, Francesco
Broccoli, Vania
author_sort Bido, Simone
collection PubMed
description 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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spelling pubmed-85562632021-11-15 Microglia-specific overexpression of α-synuclein leads to severe dopaminergic neurodegeneration by phagocytic exhaustion and oxidative toxicity Bido, Simone Muggeo, Sharon Massimino, Luca Marzi, Matteo Jacopo Giannelli, Serena Gea Melacini, Elena Nannoni, Melania Gambarè, Diana Bellini, Edoardo Ordazzo, Gabriele Rossi, Greta Maffezzini, Camilla Iannelli, Angelo Luoni, Mirko Bacigaluppi, Marco Gregori, Silvia Nicassio, Francesco Broccoli, Vania Nat Commun Article 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. Nature Publishing Group UK 2021-10-29 /pmc/articles/PMC8556263/ /pubmed/34716339 http://dx.doi.org/10.1038/s41467-021-26519-x Text en © The Author(s) 2021, corrected publication 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Bido, Simone
Muggeo, Sharon
Massimino, Luca
Marzi, Matteo Jacopo
Giannelli, Serena Gea
Melacini, Elena
Nannoni, Melania
Gambarè, Diana
Bellini, Edoardo
Ordazzo, Gabriele
Rossi, Greta
Maffezzini, Camilla
Iannelli, Angelo
Luoni, Mirko
Bacigaluppi, Marco
Gregori, Silvia
Nicassio, Francesco
Broccoli, Vania
Microglia-specific overexpression of α-synuclein leads to severe dopaminergic neurodegeneration by phagocytic exhaustion and oxidative toxicity
title Microglia-specific overexpression of α-synuclein leads to severe dopaminergic neurodegeneration by phagocytic exhaustion and oxidative toxicity
title_full Microglia-specific overexpression of α-synuclein leads to severe dopaminergic neurodegeneration by phagocytic exhaustion and oxidative toxicity
title_fullStr Microglia-specific overexpression of α-synuclein leads to severe dopaminergic neurodegeneration by phagocytic exhaustion and oxidative toxicity
title_full_unstemmed Microglia-specific overexpression of α-synuclein leads to severe dopaminergic neurodegeneration by phagocytic exhaustion and oxidative toxicity
title_short Microglia-specific overexpression of α-synuclein leads to severe dopaminergic neurodegeneration by phagocytic exhaustion and oxidative toxicity
title_sort microglia-specific overexpression of α-synuclein leads to severe dopaminergic neurodegeneration by phagocytic exhaustion and oxidative toxicity
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8556263/
https://www.ncbi.nlm.nih.gov/pubmed/34716339
http://dx.doi.org/10.1038/s41467-021-26519-x
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