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Glycation modulates glutamatergic signaling and exacerbates Parkinson’s disease-like phenotypes
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). Intere...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9038780/ https://www.ncbi.nlm.nih.gov/pubmed/35468899 http://dx.doi.org/10.1038/s41531-022-00314-x |
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author | 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_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_sort | Chegão, Ana |
collection | PubMed |
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. |
format | Online Article Text |
id | pubmed-9038780 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-90387802022-04-28 Glycation modulates glutamatergic signaling and exacerbates Parkinson’s disease-like phenotypes 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 NPJ Parkinsons Dis Article 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. Nature Publishing Group UK 2022-04-25 /pmc/articles/PMC9038780/ /pubmed/35468899 http://dx.doi.org/10.1038/s41531-022-00314-x Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/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/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article 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 Glycation modulates glutamatergic signaling and exacerbates Parkinson’s disease-like phenotypes |
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 | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9038780/ https://www.ncbi.nlm.nih.gov/pubmed/35468899 http://dx.doi.org/10.1038/s41531-022-00314-x |
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