Glycation modulates glutamatergic signaling and exacerbates Parkinson’s disease-like phenotypes

Detalhes bibliográficos
Autor(a) principal: Chegão, Ana
Data de Publicação: 2022
Outros Autores: 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
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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spelling 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
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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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