Cargando…
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...
Autores principales: | , , , , , , , , , , , , , , , , , |
---|---|
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 |
_version_ | 1784592146920112128 |
---|---|
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. |
format | Online Article Text |
id | pubmed-8556263 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT bidosimone microgliaspecificoverexpressionofasynucleinleadstoseveredopaminergicneurodegenerationbyphagocyticexhaustionandoxidativetoxicity AT muggeosharon microgliaspecificoverexpressionofasynucleinleadstoseveredopaminergicneurodegenerationbyphagocyticexhaustionandoxidativetoxicity AT massiminoluca microgliaspecificoverexpressionofasynucleinleadstoseveredopaminergicneurodegenerationbyphagocyticexhaustionandoxidativetoxicity AT marzimatteojacopo microgliaspecificoverexpressionofasynucleinleadstoseveredopaminergicneurodegenerationbyphagocyticexhaustionandoxidativetoxicity AT giannelliserenagea microgliaspecificoverexpressionofasynucleinleadstoseveredopaminergicneurodegenerationbyphagocyticexhaustionandoxidativetoxicity AT melacinielena microgliaspecificoverexpressionofasynucleinleadstoseveredopaminergicneurodegenerationbyphagocyticexhaustionandoxidativetoxicity AT nannonimelania microgliaspecificoverexpressionofasynucleinleadstoseveredopaminergicneurodegenerationbyphagocyticexhaustionandoxidativetoxicity AT gambarediana microgliaspecificoverexpressionofasynucleinleadstoseveredopaminergicneurodegenerationbyphagocyticexhaustionandoxidativetoxicity AT belliniedoardo microgliaspecificoverexpressionofasynucleinleadstoseveredopaminergicneurodegenerationbyphagocyticexhaustionandoxidativetoxicity AT ordazzogabriele microgliaspecificoverexpressionofasynucleinleadstoseveredopaminergicneurodegenerationbyphagocyticexhaustionandoxidativetoxicity AT rossigreta microgliaspecificoverexpressionofasynucleinleadstoseveredopaminergicneurodegenerationbyphagocyticexhaustionandoxidativetoxicity AT maffezzinicamilla microgliaspecificoverexpressionofasynucleinleadstoseveredopaminergicneurodegenerationbyphagocyticexhaustionandoxidativetoxicity AT iannelliangelo microgliaspecificoverexpressionofasynucleinleadstoseveredopaminergicneurodegenerationbyphagocyticexhaustionandoxidativetoxicity AT luonimirko microgliaspecificoverexpressionofasynucleinleadstoseveredopaminergicneurodegenerationbyphagocyticexhaustionandoxidativetoxicity AT bacigaluppimarco microgliaspecificoverexpressionofasynucleinleadstoseveredopaminergicneurodegenerationbyphagocyticexhaustionandoxidativetoxicity AT gregorisilvia microgliaspecificoverexpressionofasynucleinleadstoseveredopaminergicneurodegenerationbyphagocyticexhaustionandoxidativetoxicity AT nicassiofrancesco microgliaspecificoverexpressionofasynucleinleadstoseveredopaminergicneurodegenerationbyphagocyticexhaustionandoxidativetoxicity AT broccolivania microgliaspecificoverexpressionofasynucleinleadstoseveredopaminergicneurodegenerationbyphagocyticexhaustionandoxidativetoxicity |