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In vivo reduction of age-dependent neuromelanin accumulation mitigates features of Parkinson’s disease
Humans accumulate with age the dark-brown pigment neuromelanin inside specific neuronal groups. Neurons with the highest neuromelanin levels are particularly susceptible to degeneration in Parkinson’s disease, especially dopaminergic neurons of the substantia nigra, the loss of which leads to charac...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9976971/ https://www.ncbi.nlm.nih.gov/pubmed/36717986 http://dx.doi.org/10.1093/brain/awac445 |
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author | Gonzalez-Sepulveda, Marta Compte, Joan Cuadros, Thais Nicolau, Alba Guillard-Sirieix, Camille Peñuelas, Núria Lorente-Picon, Marina Parent, Annabelle Romero-Giménez, Jordi Cladera-Sastre, Joana M Laguna, Ariadna Vila, Miquel |
author_facet | Gonzalez-Sepulveda, Marta Compte, Joan Cuadros, Thais Nicolau, Alba Guillard-Sirieix, Camille Peñuelas, Núria Lorente-Picon, Marina Parent, Annabelle Romero-Giménez, Jordi Cladera-Sastre, Joana M Laguna, Ariadna Vila, Miquel |
author_sort | Gonzalez-Sepulveda, Marta |
collection | PubMed |
description | Humans accumulate with age the dark-brown pigment neuromelanin inside specific neuronal groups. Neurons with the highest neuromelanin levels are particularly susceptible to degeneration in Parkinson’s disease, especially dopaminergic neurons of the substantia nigra, the loss of which leads to characteristic motor Parkinson’s disease symptoms. In contrast to humans, neuromelanin does not appear spontaneously in most animals, including rodents, and Parkinson’s disease is an exclusively human condition. Using humanized neuromelanin-producing rodents, we recently found that neuromelanin can trigger Parkinson’s disease pathology when accumulated above a specific pathogenic threshold. Here, by taking advantage of this newly developed animal model, we assessed whether the intracellular build-up of neuromelanin that occurs with age can be slowed down in vivo to prevent or attenuate Parkinson’s disease. Because neuromelanin derives from the oxidation of free cytosolic dopamine, we enhanced dopamine vesicular encapsulation in the substantia nigra of neuromelanin-producing rats by viral vector-mediated overexpression of vesicular monoamine transporter 2 (VMAT2). This strategy reduced the formation of potentially toxic oxidized dopamine species that can convert into neuromelanin and maintained intracellular neuromelanin levels below their pathogenic threshold. Decreased neuromelanin production was associated with an attenuation of Lewy body-like inclusion formation and a long-term preservation of dopamine homeostasis, nigrostriatal neuronal integrity and motor function in these animals. Our results demonstrate the feasibility and therapeutic potential of modulating age-dependent intracellular neuromelanin production in vivo, thereby opening an unexplored path for the treatment of Parkinson’s disease and, in a broader sense, brain ageing. |
format | Online Article Text |
id | pubmed-9976971 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-99769712023-03-02 In vivo reduction of age-dependent neuromelanin accumulation mitigates features of Parkinson’s disease Gonzalez-Sepulveda, Marta Compte, Joan Cuadros, Thais Nicolau, Alba Guillard-Sirieix, Camille Peñuelas, Núria Lorente-Picon, Marina Parent, Annabelle Romero-Giménez, Jordi Cladera-Sastre, Joana M Laguna, Ariadna Vila, Miquel Brain Original Article Humans accumulate with age the dark-brown pigment neuromelanin inside specific neuronal groups. Neurons with the highest neuromelanin levels are particularly susceptible to degeneration in Parkinson’s disease, especially dopaminergic neurons of the substantia nigra, the loss of which leads to characteristic motor Parkinson’s disease symptoms. In contrast to humans, neuromelanin does not appear spontaneously in most animals, including rodents, and Parkinson’s disease is an exclusively human condition. Using humanized neuromelanin-producing rodents, we recently found that neuromelanin can trigger Parkinson’s disease pathology when accumulated above a specific pathogenic threshold. Here, by taking advantage of this newly developed animal model, we assessed whether the intracellular build-up of neuromelanin that occurs with age can be slowed down in vivo to prevent or attenuate Parkinson’s disease. Because neuromelanin derives from the oxidation of free cytosolic dopamine, we enhanced dopamine vesicular encapsulation in the substantia nigra of neuromelanin-producing rats by viral vector-mediated overexpression of vesicular monoamine transporter 2 (VMAT2). This strategy reduced the formation of potentially toxic oxidized dopamine species that can convert into neuromelanin and maintained intracellular neuromelanin levels below their pathogenic threshold. Decreased neuromelanin production was associated with an attenuation of Lewy body-like inclusion formation and a long-term preservation of dopamine homeostasis, nigrostriatal neuronal integrity and motor function in these animals. Our results demonstrate the feasibility and therapeutic potential of modulating age-dependent intracellular neuromelanin production in vivo, thereby opening an unexplored path for the treatment of Parkinson’s disease and, in a broader sense, brain ageing. Oxford University Press 2023-01-30 /pmc/articles/PMC9976971/ /pubmed/36717986 http://dx.doi.org/10.1093/brain/awac445 Text en © The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com |
spellingShingle | Original Article Gonzalez-Sepulveda, Marta Compte, Joan Cuadros, Thais Nicolau, Alba Guillard-Sirieix, Camille Peñuelas, Núria Lorente-Picon, Marina Parent, Annabelle Romero-Giménez, Jordi Cladera-Sastre, Joana M Laguna, Ariadna Vila, Miquel In vivo reduction of age-dependent neuromelanin accumulation mitigates features of Parkinson’s disease |
title |
In vivo reduction of age-dependent neuromelanin accumulation mitigates features of Parkinson’s disease |
title_full |
In vivo reduction of age-dependent neuromelanin accumulation mitigates features of Parkinson’s disease |
title_fullStr |
In vivo reduction of age-dependent neuromelanin accumulation mitigates features of Parkinson’s disease |
title_full_unstemmed |
In vivo reduction of age-dependent neuromelanin accumulation mitigates features of Parkinson’s disease |
title_short |
In vivo reduction of age-dependent neuromelanin accumulation mitigates features of Parkinson’s disease |
title_sort | in vivo reduction of age-dependent neuromelanin accumulation mitigates features of parkinson’s disease |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9976971/ https://www.ncbi.nlm.nih.gov/pubmed/36717986 http://dx.doi.org/10.1093/brain/awac445 |
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