Glycation modulates glutamatergic signaling and exacerbates Parkinson’s disease-like phenotypes
| Autor(a) principal: | |
|---|---|
| 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/10362/139407 |
Resumo: | Funding Information: 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). Funding Information: We would like to thank the vivarium and behavioral facilities at Instituto de Medicina Molecular?Jo?o Lobo Antunes for all the support. We also thank Prof. Rosalina Fonseca, Prof. S?lvia V. Conde, Dr Rita Machado de Oliveira, Dr Nat?lia Madeira, Dr Liliana Lopes, Dr Tatiana Burrinha, and Dr Catarina Perdig?o for fruitful discussions. We thank Dr Manuela Correia for all the laboratory support. We are deeply thankful to Prof. Jos? Ramalho for kindly allowing the use of equipment for protein analysis. This study was supported by Funda??o para a Ci?ncia e Tecnologia (FCT) PTDC/NEU-OSD/5644/2014, by iNOVA4Health UIDB/04462/2020 and UIDP/04462/2020, a program financially supported by FCT/Minist?rio da Ci?ncia, 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). Publisher Copyright: © 2022, The Author(s). |
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Glycation modulates glutamatergic signaling and exacerbates Parkinson’s disease-like phenotypesNeurologyClinical NeurologyCellular and Molecular NeuroscienceSDG 3 - Good Health and Well-beingFunding Information: 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). Funding Information: We would like to thank the vivarium and behavioral facilities at Instituto de Medicina Molecular?Jo?o Lobo Antunes for all the support. We also thank Prof. Rosalina Fonseca, Prof. S?lvia V. Conde, Dr Rita Machado de Oliveira, Dr Nat?lia Madeira, Dr Liliana Lopes, Dr Tatiana Burrinha, and Dr Catarina Perdig?o for fruitful discussions. We thank Dr Manuela Correia for all the laboratory support. We are deeply thankful to Prof. Jos? Ramalho for kindly allowing the use of equipment for protein analysis. This study was supported by Funda??o para a Ci?ncia e Tecnologia (FCT) PTDC/NEU-OSD/5644/2014, by iNOVA4Health UIDB/04462/2020 and UIDP/04462/2020, a program financially supported by FCT/Minist?rio da Ci?ncia, 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). Publisher Copyright: © 2022, The Author(s).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.NOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM)Centro de Estudos de Doenças Crónicas (CEDOC)Instituto de Tecnologia Química e Biológica António Xavier (ITQB)RUNChegão, AnaGuarda, MarianaAlexandre, Bruno M.Shvachiy, LianaTemido-Ferreira, MarianaMarques-Morgado, InêsFernandes Gomes, BárbaraMatthiesen, RuneLopes, Luísa V.Florindo, Pedro R.Gomes, Ricardo A.Gomes-Alves, PatríciaCoelho, Joana E.Outeiro, Tiago FlemingVicente Miranda, Hugo2022-06-03T22:31:14Z2022-04-252022-04-25T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10362/139407eng2373-8057PURE: 43781124https://doi.org/10.1038/s41531-022-00314-xinfo: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:RCAAP2024-03-11T05:16:46Zoai:run.unl.pt:10362/139407Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-20T03:49:26.270251Repositório 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 Neurology Clinical Neurology Cellular and Molecular Neuroscience SDG 3 - Good Health and Well-being |
| 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, Luísa V. Florindo, Pedro R. Gomes, Ricardo A. Gomes-Alves, Patrícia Coelho, Joana E. Outeiro, Tiago Fleming 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, Luísa V. Florindo, Pedro R. Gomes, Ricardo A. Gomes-Alves, Patrícia Coelho, Joana E. Outeiro, Tiago Fleming 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 |
NOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM) Centro de Estudos de Doenças Crónicas (CEDOC) Instituto de Tecnologia Química e Biológica António Xavier (ITQB) RUN |
| 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, Luísa V. Florindo, Pedro R. Gomes, Ricardo A. Gomes-Alves, Patrícia Coelho, Joana E. Outeiro, Tiago Fleming Vicente Miranda, Hugo |
| dc.subject.por.fl_str_mv |
Neurology Clinical Neurology Cellular and Molecular Neuroscience SDG 3 - Good Health and Well-being |
| topic |
Neurology Clinical Neurology Cellular and Molecular Neuroscience SDG 3 - Good Health and Well-being |
| description |
Funding Information: 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). Funding Information: We would like to thank the vivarium and behavioral facilities at Instituto de Medicina Molecular?Jo?o Lobo Antunes for all the support. We also thank Prof. Rosalina Fonseca, Prof. S?lvia V. Conde, Dr Rita Machado de Oliveira, Dr Nat?lia Madeira, Dr Liliana Lopes, Dr Tatiana Burrinha, and Dr Catarina Perdig?o for fruitful discussions. We thank Dr Manuela Correia for all the laboratory support. We are deeply thankful to Prof. Jos? Ramalho for kindly allowing the use of equipment for protein analysis. This study was supported by Funda??o para a Ci?ncia e Tecnologia (FCT) PTDC/NEU-OSD/5644/2014, by iNOVA4Health UIDB/04462/2020 and UIDP/04462/2020, a program financially supported by FCT/Minist?rio da Ci?ncia, 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). Publisher Copyright: © 2022, The Author(s). |
| publishDate |
2022 |
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2022-06-03T22:31:14Z 2022-04-25 2022-04-25T00:00:00Z |
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info:eu-repo/semantics/publishedVersion |
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info:eu-repo/semantics/article |
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article |
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http://hdl.handle.net/10362/139407 |
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eng |
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eng |
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2373-8057 PURE: 43781124 https://doi.org/10.1038/s41531-022-00314-x |
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info:eu-repo/semantics/openAccess |
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openAccess |
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