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

View ORCID ProfileAna Chegão, View ORCID ProfileMariana Guarda, View ORCID ProfileBruno M. Alexandre, View ORCID ProfileLiana Shvachiy, View ORCID ProfileMariana Temido-Ferreira, View ORCID ProfileInês Marques-Morgado, View ORCID ProfileBárbara Fernandes Gomes, View ORCID ProfileRune Matthiesen, View ORCID ProfileLuísa V. Lopes, View ORCID ProfilePedro R. Florindo, View ORCID ProfileRicardo Anjos-Gomes, View ORCID ProfilePatrícia Gomes-Alves, View ORCID ProfileJoana E. Coelho, View ORCID ProfileTiago Fleming Outeiro, View ORCID ProfileHugo Vicente Miranda
doi: https://doi.org/10.1101/2021.08.24.457507
Ana Chegão
1CEDOC, NOVA Medical School, NMS, Universidade NOVA de Lisboa, 1169-056, Lisboa, Portugal
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  • ORCID record for Ana Chegão
Mariana Guarda
1CEDOC, NOVA Medical School, NMS, Universidade NOVA de Lisboa, 1169-056, Lisboa, Portugal
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Bruno M. Alexandre
2Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa, Av. Da República, 2780-157 Oeiras, Portugal
3iBET, Instituto de Biologia Experimental e Tecnológica, Apartado 12, 2781-901 Oeiras, Portugal
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Liana Shvachiy
4Department of Experimental Neurodegeneration, Center for Biostructural Imaging of Neurodegeneration, University Medical Center Göttingen, Germany
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Mariana Temido-Ferreira
5Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina da Universidade de Lisboa, Portugal
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Inês Marques-Morgado
5Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina da Universidade de Lisboa, Portugal
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Bárbara Fernandes Gomes
1CEDOC, NOVA Medical School, NMS, Universidade NOVA de Lisboa, 1169-056, Lisboa, Portugal
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Rune Matthiesen
1CEDOC, NOVA Medical School, NMS, Universidade NOVA de Lisboa, 1169-056, Lisboa, Portugal
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Luísa V. Lopes
5Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina da Universidade de Lisboa, Portugal
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Pedro R. Florindo
6Instituto de Investigação do Medicamento (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, 1649-003 Lisboa, Portugal
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Ricardo Anjos-Gomes
2Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa, Av. Da República, 2780-157 Oeiras, Portugal
3iBET, Instituto de Biologia Experimental e Tecnológica, Apartado 12, 2781-901 Oeiras, Portugal
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Patrícia Gomes-Alves
2Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa, Av. Da República, 2780-157 Oeiras, Portugal
3iBET, Instituto de Biologia Experimental e Tecnológica, Apartado 12, 2781-901 Oeiras, Portugal
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Joana E. Coelho
5Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina da Universidade de Lisboa, Portugal
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Tiago Fleming Outeiro
4Department of Experimental Neurodegeneration, Center for Biostructural Imaging of Neurodegeneration, University Medical Center Göttingen, Germany
7Max Planck Institute for Experimental Medicine, 37075 Göttingen, Germany
8Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, NE2 4HH, United Kingdom
9Scientific employee with an honorary contract at German Center for Neurodegenerative Diseases (DZNE), 37075 Göttingen, Germany
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  • For correspondence: hmvmiranda@nms.unl.pt touteir@gwdg.de
Hugo Vicente Miranda
1CEDOC, NOVA Medical School, NMS, Universidade NOVA de Lisboa, 1169-056, Lisboa, Portugal
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  • For correspondence: hmvmiranda@nms.unl.pt touteir@gwdg.de
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Abstract

Alpha-synuclein (aSyn) is assumed to be 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 and, one common molecular alteration among these disorders is an age-associated increase in protein glycation. Thus, we hypothesized that glycation-induced dysfunction of neuronal pathways might be an underlying molecular cause of synucleinopathies. Here, we evaluated if increased brain glycation modulated motor and/or non-motor phenotypes in a mouse model of synucleinopathies. In addition, we dissected the specific impact of methylglyoxal (MGO, a glycating agent) in mice overexpressing aSyn in the brain, and unveiled the major molecular pathways altered. Age-matched (16 weeks old) male aSyn transgenic (Thy1-aSyn) or WT mice received a single dose of MGO or vehicle via intracerebroventricular (ICV) injection. Behavioural phenotypes were analysed 4 weeks post-treatment, and, at the end of the tests, biochemical and histological studies were conducted on brain tissue. We found that glycation potentiates motor dysfunction, assessed by vertical pole, rotarod and hindlimb clasping tests in Thy1-aSyn mice. In addition, it induces cognitive impairment (Y maze test), olfactory disturbances (block test), and colonic dysfunction. These behavioural changes were accompanied by the accumulation of aSyn in the midbrain, striatum, and prefrontal cortex, and by an overall increase in glycation in the midbrain and cerebellum. Furthermore, MGO induced neuronal and dopaminergic cell loss in the midbrain of Thy1-aSyn mice. Quantitative proteomic analysis revealed that, in Thy1-aSyn mice, MGO mainly impacts on glutamatergic proteins in the midbrain, but not in the prefrontal cortex, where it mainly affects the electron transport chain. Among the altered proteins in the midbrain, we found an upregulation of N-Methyl-D-Aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptors levels, glutaminase, vesicle glutamate transporter (VGLUT), and the excitatory amino acid transporter (EAAT1), suggesting potentiation of glutamatergic signalling. Overall, we demonstrated that MGO-induced glycation accelerates Parkinsonian-like sensorimotor and cognitive alterations. The increase in glutamatergic-related proteins in the midbrain may represent a compensatory mechanism to the MGO-induced dopaminergic neurodegeneration. Our study sheds light into the enhanced vulnerability of the midbrain in Parkinson’s disease-related synaptic dysfunction that, ultimately leads to cell loss, and provides molecular insight into the observation that glycation suppressors and anti-glutamatergic drugs hold promise as disease-modifying therapies for synucleinopathies.

Competing Interest Statement

The authors have declared no competing interest.

  • Abbreviations

    aSyn
    Alpha-synuclein
    AGEs
    advanced glycation end products
    AMPA
    α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
    BG
    basal ganglia
    CEL
    N(epsilon)-(carboxyethyl)lysine
    EAAT1
    excitatory amino acid transporter
    GO
    Gene Ontology
    ICV
    intracerebroventricular
    KEGG
    Kyoto Encyclopaedia of Genes and Genomes
    LB
    Lewy bodies
    LN
    Lewy neurites
    MGO
    methylglyoxal
    NMDA
    N-Methyl-D-Aspartate (NMDA)
    PTMs
    posttranslational modifications
    SNpc
    substantia nigra pars compacta
    SWATH-MS
    sequential window acquisition of all theoretical mass spectra
    TH
    tyrosine hydroxylase
    VGLUT
    vesicle glutamate transporter
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    Posted August 25, 2021.
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    Glycation modulates glutamatergic signalling and exacerbates Parkinson’s disease-like phenotypes
    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 Anjos-Gomes, Patrícia Gomes-Alves, Joana E. Coelho, Tiago Fleming Outeiro, Hugo Vicente Miranda
    bioRxiv 2021.08.24.457507; doi: https://doi.org/10.1101/2021.08.24.457507
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    Glycation modulates glutamatergic signalling and exacerbates Parkinson’s disease-like phenotypes
    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 Anjos-Gomes, Patrícia Gomes-Alves, Joana E. Coelho, Tiago Fleming Outeiro, Hugo Vicente Miranda
    bioRxiv 2021.08.24.457507; doi: https://doi.org/10.1101/2021.08.24.457507

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