Publicação
Glycation modulates glutamatergic signaling and exacerbates Parkinson’s disease-like phenotypes
| Resumo: | 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. |
|---|---|
| Autores principais: | Chegão, Ana |
| Outros Autores: | Guarda, Mariana; Alexandre, Bruno M.; Shvachiy, Liana; Temido-Ferreira, Mariana; Marques-Morgado, Inês; Fernandes Gomes, Bárbara; Matthiesen, Rune; Matthiesen, Rune; Lopes, Luísa V.; Florindo, Pedro R.; Gomes, Ricardo A.; Gomes-Alves, Patrícia; Coelho, Joana E.; Outeiro, Tiago Fleming; Vicente Miranda, Hugo |
| Assunto: | Neurology Clinical Neurology Cellular and Molecular Neuroscience SDG 3 - Good Health and Well-being |
| Ano: | 2022 |
| País: | Portugal |
| Tipo de documento: | artigo |
| Tipo de acesso: | acesso aberto |
| Instituição associada: | Universidade Nova de Lisboa |
| Idioma: | inglês |
| Origem: | Repositório Institucional da UNL |
| _version_ | 1879446113578123264 |
|---|---|
| author | Chegão, Ana |
| author2 | Guarda, Mariana Alexandre, Bruno M. Shvachiy, Liana Temido-Ferreira, Mariana Marques-Morgado, Inês Fernandes Gomes, Bárbara Matthiesen, Rune 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 author |
| author_facet | Chegão, Ana Guarda, Mariana Alexandre, Bruno M. Shvachiy, Liana Temido-Ferreira, Mariana Marques-Morgado, Inês Fernandes Gomes, Bárbara Matthiesen, Rune 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 |
| contributor_name_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) Springer Nature RUN |
| country_str | PT |
| creators_json_txt | [{\"Person.name\":\"Chegão, Ana\"},{\"Person.name\":\"Guarda, Mariana\"},{\"Person.name\":\"Alexandre, Bruno M.\"},{\"Person.name\":\"Shvachiy, Liana\"},{\"Person.name\":\"Temido-Ferreira, Mariana\"},{\"Person.name\":\"Marques-Morgado, Inês\"},{\"Person.name\":\"Fernandes Gomes, Bárbara\"},{\"Person.name\":\"Matthiesen, Rune\"},{\"Person.name\":\"Matthiesen, Rune\",\"Person.identifier.cienciaID\":\"BB1A-A606-EE77\",\"Person.identifier.orcid\":\"0000-0002-6353-2616\",\"Person.identifier.scopusAuthorID\":\"9741897800\"},{\"Person.name\":\"Lopes, Luísa V.\"},{\"Person.name\":\"Florindo, Pedro R.\"},{\"Person.name\":\"Gomes, Ricardo A.\"},{\"Person.name\":\"Gomes-Alves, Patrícia\"},{\"Person.name\":\"Coelho, Joana E.\"},{\"Person.name\":\"Outeiro, Tiago Fleming\"},{\"Person.name\":\"Vicente Miranda, Hugo\"}] |
| datacite.contributors.contributor.contributorName.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) Springer Nature RUN |
| datacite.creators.creator.creatorName.fl_str_mv | Chegão, Ana Guarda, Mariana Alexandre, Bruno M. Shvachiy, Liana Temido-Ferreira, Mariana Marques-Morgado, Inês Fernandes Gomes, Bárbara Matthiesen, Rune Matthiesen, Rune Lopes, Luísa V. Florindo, Pedro R. Gomes, Ricardo A. Gomes-Alves, Patrícia Coelho, Joana E. Outeiro, Tiago Fleming Vicente Miranda, Hugo |
| datacite.date.Accepted.fl_str_mv | 2022-04-25T00:00:00Z |
| datacite.date.available.fl_str_mv | 2022-06-03T22:31:14Z |
| datacite.date.embargoed.fl_str_mv | 2022-06-03T22:31:14Z |
| datacite.rights.fl_str_mv | http://purl.org/coar/access_right/c_abf2 |
| datacite.subjects.subject.fl_str_mv | Neurology Clinical Neurology Cellular and Molecular Neuroscience SDG 3 - Good Health and Well-being |
| datacite.titles.title.fl_str_mv | Glycation modulates glutamatergic signaling and exacerbates Parkinson’s disease-like phenotypes |
| 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) Springer Nature RUN |
| dc.creator.none.fl_str_mv | Chegão, Ana Guarda, Mariana Alexandre, Bruno M. Shvachiy, Liana Temido-Ferreira, Mariana Marques-Morgado, Inês Fernandes Gomes, Bárbara Matthiesen, Rune Matthiesen, Rune Lopes, Luísa V. Florindo, Pedro R. Gomes, Ricardo A. Gomes-Alves, Patrícia Coelho, Joana E. Outeiro, Tiago Fleming Vicente Miranda, Hugo |
| dc.date.Accepted.fl_str_mv | 2022-04-25T00:00:00Z |
| dc.date.available.fl_str_mv | 2022-06-03T22:31:14Z |
| dc.date.embargoed.fl_str_mv | 2022-06-03T22:31:14Z |
| dc.format.none.fl_str_mv | application/pdf |
| dc.identifier.none.fl_str_mv | http://hdl.handle.net/10362/139407 |
| dc.language.none.fl_str_mv | eng |
| dc.rights.none.fl_str_mv | http://purl.org/coar/access_right/c_abf2 |
| dc.subject.none.fl_str_mv | Neurology Clinical Neurology Cellular and Molecular Neuroscience SDG 3 - Good Health and Well-being |
| dc.title.fl_str_mv | Glycation modulates glutamatergic signaling and exacerbates Parkinson’s disease-like phenotypes |
| dc.type.none.fl_str_mv | http://purl.org/coar/resource_type/c_6501 |
| description | 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. |
| dirty | 0 |
| eu_rights_str_mv | openAccess |
| format | article |
| fulltext.url.fl_str_mv | https://run.unl.pt/bitstreams/1d7173d1-c05f-4afd-bb98-ed3007831b81/download |
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| identifier.url.fl_str_mv | http://hdl.handle.net/10362/139407 |
| inst_facet_str | urn:organizationAcronym:unl{{{_:::_}}}Universidade Nova de Lisboa |
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| institution | Universidade Nova de Lisboa |
| instname_str | Universidade Nova de Lisboa |
| language | eng |
| network_acronym_str | run |
| network_name_str | Repositório Institucional da UNL |
| oai_identifier_str | oai:run.unl.pt:10362/139407 |
| organization_str_mv | urn:organizationAcronym:unl |
| person_str_mv | Chegão, Ana Guarda, Mariana Alexandre, Bruno M. Shvachiy, Liana Temido-Ferreira, Mariana Marques-Morgado, Inês Fernandes Gomes, Bárbara Matthiesen, Rune Matthiesen, Rune Matthiesen, Rune https://www.ciencia-id.pt/BB1A-A606-EE77 BB1A-A606-EE77 http://orcid.org/0000-0002-6353-2616 0000-0002-6353-2616 Lopes, Luísa V. Florindo, Pedro R. Gomes, Ricardo A. Gomes-Alves, Patrícia Coelho, Joana E. Outeiro, Tiago Fleming Vicente Miranda, Hugo |
| publishDate | 2022 |
| repo_facet_str | urn:repositoryAcronym:run{{{_:::_}}}Repositório Institucional da UNL |
| reponame_str | Repositório Institucional da UNL |
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| service_str_mv | urn:repositoryAcronym:run |
| spelling | engenAlpha-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.application/pdfenGlycation modulates glutamatergic signaling and exacerbates Parkinson’s disease-like phenotypesChegão, AnaGuarda, MarianaAlexandre, Bruno M.Shvachiy, LianaTemido-Ferreira, MarianaMarques-Morgado, InêsFernandes Gomes, BárbaraMatthiesen, RunePersonalMatthiesen, RuneDSpacehttp://dspace.org/items/67181d3c-b83e-4151-9a74-0ea14aeb7f05DSpacehttp://dspace.org/items/67181d3c-b83e-4151-9a74-0ea14aeb7f05MatthiesenRuneCiência IDhttps://www.ciencia-id.ptBB1A-A606-EE77ORCIDhttp://orcid.org0000-0002-6353-2616Scopus Author IDhttps://www.scopus.com9741897800Lopes, Luísa V.Florindo, Pedro R.Gomes, Ricardo A.Gomes-Alves, PatríciaCoelho, Joana E.Outeiro, Tiago FlemingVicente Miranda, HugoNOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM)Centro de Estudos de Doenças Crónicas (CEDOC)Instituto de Tecnologia Química e Biológica António Xavier (ITQB)Springer NatureHostingInstitutionOrganizationalRUNe-mailmailto:run@unl.ptrun@unl.ptISSNIsPartOf2373-8057URNIsPartOfPURE: 43781124URNIsPartOfPURE UUID: 353a0718-667d-4161-8c59-ea7ddc6f7b87URNIsPartOfScopus: 85128843802URNIsPartOfWOS: 000787311300001DOIIsPartOf10.1038/s41531-022-00314-x2022-06-03T22:31:14Z2022-04-252022-04-25T00:00:00ZHandlehttp://hdl.handle.net/10362/139407http://purl.org/coar/access_right/c_abf2open accessNeurologyClinical NeurologyCellular and Molecular NeuroscienceSDG 3 - Good Health and Well-being6405256 bytesliteraturehttp://purl.org/coar/resource_type/c_6501journal articlehttp://purl.org/coar/access_right/c_abf2application/pdffulltexthttps://run.unl.pt/bitstreams/1d7173d1-c05f-4afd-bb98-ed3007831b81/download |
| 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 |
| status | SINGLETON |
| subject.fl_str_mv | Neurology Clinical Neurology Cellular and Molecular Neuroscience SDG 3 - Good Health and Well-being |
| title | 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_short | Glycation modulates glutamatergic signaling and exacerbates Parkinson’s disease-like phenotypes |
| title_sort | Glycation modulates glutamatergic signaling and exacerbates Parkinson’s disease-like phenotypes |
| topic | Neurology Clinical Neurology Cellular and Molecular Neuroscience SDG 3 - Good Health and Well-being |
| topic_facet | Neurology Clinical Neurology Cellular and Molecular Neuroscience SDG 3 - Good Health and Well-being |
| url | http://hdl.handle.net/10362/139407 |
| visible | 1 |
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