Glycation modulates glutamatergic signaling and exacerbates Parkinson’s disease-like phenotypes
Autor(a) principal: | |
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Data de Publicação: | 2022 |
Outros Autores: | , , , , , , , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | http://hdl.handle.net/10451/52572 |
Resumo: | © The Author(s) 2022. 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/. |
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Glycation modulates glutamatergic signaling and exacerbates Parkinson’s disease-like phenotypes© The Author(s) 2022. 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/.Alpha-synuclein (aSyn) is a central player in the pathogenesis of synucleinopathies due to its accumulation in typical protein aggregates in the brain. However, it is still unclear how it contributes to neurodegeneration. Type-2 diabetes mellitus is a risk factor for Parkinson's disease (PD). Interestingly, a common molecular alteration among these disorders is the age-associated increase in protein glycation. We hypothesized that glycation-induced neuronal dysfunction is a contributing factor in synucleinopathies. Here, we dissected the impact of methylglyoxal (MGO, a glycating agent) in mice overexpressing aSyn in the brain. We found that MGO-glycation potentiates motor, cognitive, olfactory, and colonic dysfunction in aSyn transgenic (Thy1-aSyn) mice that received a single dose of MGO via intracerebroventricular injection. aSyn accumulates in the midbrain, striatum, and prefrontal cortex, and protein glycation is increased in the cerebellum and midbrain. SWATH mass spectrometry analysis, used to quantify changes in the brain proteome, revealed that MGO mainly increase glutamatergic-associated proteins in the midbrain (NMDA, AMPA, glutaminase, VGLUT and EAAT1), but not in the prefrontal cortex, where it mainly affects the electron transport chain. The glycated proteins in the midbrain of MGO-injected Thy1-aSyn mice strongly correlate with PD and dopaminergic pathways. Overall, we demonstrated that MGO-induced glycation accelerates PD-like sensorimotor and cognitive alterations and suggest that the increase of glutamatergic signaling may underly these events. Our study sheds new light into the enhanced vulnerability of the midbrain in PD-related synaptic dysfunction and suggests that glycation suppressors and anti-glutamatergic drugs may hold promise as disease-modifying therapies for synucleinopathies.This study was supported by Fundação para a Ciência e Tecnologia (FCT) PTDC/NEU-OSD/5644/2014, by iNOVA4Health UIDB/04462/2020 and UIDP/04462/2020, a program financially supported by FCT/Ministério da Ciência, Tecnologia e Ensino Superior, through national funds; and by Sociedade Portuguesa de Diabetologia. The authors were supported by: A.C. (FCT, PD/BD/136863/2018; ProRegeM – PhD programme, mechanisms of disease and regenerative medicine); B.F.G. (PTDC/NEU-OSD/5644/2014); L.S. (SFRH/BD/143286/2019). T.F.O. is supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy - EXC 2067/1- 390729940, and by SFB1286 (B8).Springer NatureRepositório da Universidade de LisboaChegão, AnaGuarda, MarianaAlexandre, Bruno M.Shvachiy, LianaTemido Ferreira, MarianaMarques-Morgado, InêsFernandes Gomes, BárbaraMatthiesen, RuneLopes, Luisa V.Florindo, Pedro R.Gomes, Ricardo A.Gomes-Alves, PatríciaCoelho, Joana EOuteiro, TiagoVicente Miranda, Hugo2022-04-27T15:52:39Z20222022-01-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10451/52572engNPJ Parkinsons Dis. 2022 Apr 25;8(1):5110.1038/s41531-022-00314-x2373-8057info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-11-08T16:57:50Zoai:repositorio.ul.pt:10451/52572Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T22:03:38.685956Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
dc.title.none.fl_str_mv |
Glycation modulates glutamatergic signaling and exacerbates Parkinson’s disease-like phenotypes |
title |
Glycation modulates glutamatergic signaling and exacerbates Parkinson’s disease-like phenotypes |
spellingShingle |
Glycation modulates glutamatergic signaling and exacerbates Parkinson’s disease-like phenotypes Chegão, Ana |
title_short |
Glycation modulates glutamatergic signaling and exacerbates Parkinson’s disease-like phenotypes |
title_full |
Glycation modulates glutamatergic signaling and exacerbates Parkinson’s disease-like phenotypes |
title_fullStr |
Glycation modulates glutamatergic signaling and exacerbates Parkinson’s disease-like phenotypes |
title_full_unstemmed |
Glycation modulates glutamatergic signaling and exacerbates Parkinson’s disease-like phenotypes |
title_sort |
Glycation modulates glutamatergic signaling and exacerbates Parkinson’s disease-like phenotypes |
author |
Chegão, Ana |
author_facet |
Chegão, Ana Guarda, Mariana Alexandre, Bruno M. Shvachiy, Liana Temido Ferreira, Mariana Marques-Morgado, Inês Fernandes Gomes, Bárbara Matthiesen, Rune Lopes, Luisa V. Florindo, Pedro R. Gomes, Ricardo A. Gomes-Alves, Patrícia Coelho, Joana E Outeiro, Tiago Vicente Miranda, Hugo |
author_role |
author |
author2 |
Guarda, Mariana Alexandre, Bruno M. Shvachiy, Liana Temido Ferreira, Mariana Marques-Morgado, Inês Fernandes Gomes, Bárbara Matthiesen, Rune Lopes, Luisa V. Florindo, Pedro R. Gomes, Ricardo A. Gomes-Alves, Patrícia Coelho, Joana E Outeiro, Tiago Vicente Miranda, Hugo |
author2_role |
author author author author author author author author author author author author author author |
dc.contributor.none.fl_str_mv |
Repositório da Universidade de Lisboa |
dc.contributor.author.fl_str_mv |
Chegão, Ana Guarda, Mariana Alexandre, Bruno M. Shvachiy, Liana Temido Ferreira, Mariana Marques-Morgado, Inês Fernandes Gomes, Bárbara Matthiesen, Rune Lopes, Luisa V. Florindo, Pedro R. Gomes, Ricardo A. Gomes-Alves, Patrícia Coelho, Joana E Outeiro, Tiago Vicente Miranda, Hugo |
description |
© The Author(s) 2022. 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/. |
publishDate |
2022 |
dc.date.none.fl_str_mv |
2022-04-27T15:52:39Z 2022 2022-01-01T00:00:00Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/10451/52572 |
url |
http://hdl.handle.net/10451/52572 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
NPJ Parkinsons Dis. 2022 Apr 25;8(1):51 10.1038/s41531-022-00314-x 2373-8057 |
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info:eu-repo/semantics/openAccess |
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openAccess |
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application/pdf |
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Springer Nature |
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Springer Nature |
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