Glycation modulates glutamatergic signaling and exacerbates Parkinson’s disease-like phenotypes
Abstract 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...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2022-04-01
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| Series: | npj Parkinson's Disease |
| Online Access: | https://doi.org/10.1038/s41531-022-00314-x |
| _version_ | 1827608723347996672 |
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| author | Ana Chegão Mariana Guarda Bruno M. Alexandre Liana Shvachiy Mariana Temido-Ferreira Inês Marques-Morgado Bárbara Fernandes Gomes Rune Matthiesen Luísa V. Lopes Pedro R. Florindo Ricardo A. Gomes Patrícia Gomes-Alves Joana E. Coelho Tiago Fleming Outeiro Hugo Vicente Miranda |
| author_facet | Ana Chegão Mariana Guarda Bruno M. Alexandre Liana Shvachiy Mariana Temido-Ferreira Inês Marques-Morgado Bárbara Fernandes Gomes Rune Matthiesen Luísa V. Lopes Pedro R. Florindo Ricardo A. Gomes Patrícia Gomes-Alves Joana E. Coelho Tiago Fleming Outeiro Hugo Vicente Miranda |
| author_sort | Ana Chegão |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-03-09T07:18:45Z |
| format | Article |
| id | doaj.art-505e44be1dd441bfb7ad630258f5cddb |
| institution | Directory Open Access Journal |
| issn | 2373-8057 |
| language | English |
| last_indexed | 2024-03-09T07:18:45Z |
| publishDate | 2022-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Parkinson's Disease |
| spelling | doaj.art-505e44be1dd441bfb7ad630258f5cddb2023-12-03T07:58:32ZengNature Portfolionpj Parkinson's Disease2373-80572022-04-018112210.1038/s41531-022-00314-xGlycation modulates glutamatergic signaling and exacerbates Parkinson’s disease-like phenotypesAna Chegão0Mariana Guarda1Bruno M. Alexandre2Liana Shvachiy3Mariana Temido-Ferreira4Inês Marques-Morgado5Bárbara Fernandes Gomes6Rune Matthiesen7Luísa V. Lopes8Pedro R. Florindo9Ricardo A. Gomes10Patrícia Gomes-Alves11Joana E. Coelho12Tiago Fleming Outeiro13Hugo Vicente Miranda14CEDOC, NOVA Medical School, NMS, Universidade NOVA de LisboaCEDOC, NOVA Medical School, NMS, Universidade NOVA de LisboaInstituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de LisboaDepartment of Experimental Neurodegeneration, Center for Biostructural Imaging of Neurodegeneration, University Medical Center GöttingenInstituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina da Universidade de LisboaInstituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina da Universidade de LisboaCEDOC, NOVA Medical School, NMS, Universidade NOVA de LisboaCEDOC, NOVA Medical School, NMS, Universidade NOVA de LisboaInstituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina da Universidade de LisboaInstituto de Investigação do Medicamento (iMed.ULisboa), Faculdade de Farmácia, Universidade de LisboaInstituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de LisboaInstituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de LisboaInstituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina da Universidade de LisboaDepartment of Experimental Neurodegeneration, Center for Biostructural Imaging of Neurodegeneration, University Medical Center GöttingenCEDOC, NOVA Medical School, NMS, Universidade NOVA de LisboaAbstract 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.https://doi.org/10.1038/s41531-022-00314-x |
| spellingShingle | Ana Chegão Mariana Guarda Bruno M. Alexandre Liana Shvachiy Mariana Temido-Ferreira Inês Marques-Morgado Bárbara Fernandes Gomes Rune Matthiesen Luísa V. Lopes Pedro R. Florindo Ricardo A. Gomes Patrícia Gomes-Alves Joana E. Coelho Tiago Fleming Outeiro Hugo Vicente Miranda Glycation modulates glutamatergic signaling and exacerbates Parkinson’s disease-like phenotypes npj Parkinson's Disease |
| 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 |
| url | https://doi.org/10.1038/s41531-022-00314-x |
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