Genetic suppression of collapsin response mediator protein 2 phosphorylation improves outcome in methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinson’s model mice

Kentaro Togashi, Masaya Hasegawa, Jun Nagai, Aine Tonouchi, Daiki Masukawa, Kenneth Hensley, Yoshio Goshima, Toshio Ohshima

    研究成果: Article

    3 引用 (Scopus)

    抄録

    Parkinson's disease (PD) is a common neurodegenerative disorder characterized by slow and progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc). Levodopa (l-Dopa), the current main treatment for PD, supplies dopamine, but it does not prevent neurodegeneration. There is thus no promising remedy for PD. Recent in vitro study showed the increase in the phosphorylation levels of Collapsin Response Mediator Protein 2 (CRMP2) is involved in dopaminergic axon degeneration. In the present study, we report elevation of CRMP2 phosphorylation in dopaminergic neurons in SNc after challenge with the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a common model for PD. Genetic suppression of CRMP2 phosphorylation by mutation of the obligatory Cyclin-dependent kinase 5 (Cdk5)-targeted serine-522 site prevented axonal degradation in the nigrostriatal pathway of transgenic mice. As a result, the degree of MPTP-induced motor impairment in the rotarod test was suppressed. These results suggest that suppression of CRMP2 phosphorylation may be a novel therapeutic target for PD.

    元の言語English
    ジャーナルGenes to Cells
    DOI
    出版物ステータスAccepted/In press - 2018 1 1

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    Genetic Suppression
    Parkinson Disease
    Phosphorylation
    Dopaminergic Neurons
    Rotarod Performance Test
    Cyclin-Dependent Kinase 5
    1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
    Dihydroxyphenylalanine
    Neurotoxins
    Levodopa
    Neurodegenerative Diseases
    Serine
    Transgenic Mice
    Axons
    Dopamine
    4-phenyl-1,2,3,6-tetrahydropyridine
    collapsin response mediator protein-2
    Mutation

    ASJC Scopus subject areas

    • Genetics
    • Cell Biology

    これを引用

    Genetic suppression of collapsin response mediator protein 2 phosphorylation improves outcome in methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinson’s model mice. / Togashi, Kentaro; Hasegawa, Masaya; Nagai, Jun; Tonouchi, Aine; Masukawa, Daiki; Hensley, Kenneth; Goshima, Yoshio; Ohshima, Toshio.

    :: Genes to Cells, 01.01.2018.

    研究成果: Article

    Togashi, Kentaro ; Hasegawa, Masaya ; Nagai, Jun ; Tonouchi, Aine ; Masukawa, Daiki ; Hensley, Kenneth ; Goshima, Yoshio ; Ohshima, Toshio. / Genetic suppression of collapsin response mediator protein 2 phosphorylation improves outcome in methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinson’s model mice. :: Genes to Cells. 2018.
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    abstract = "Parkinson's disease (PD) is a common neurodegenerative disorder characterized by slow and progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc). Levodopa (l-Dopa), the current main treatment for PD, supplies dopamine, but it does not prevent neurodegeneration. There is thus no promising remedy for PD. Recent in vitro study showed the increase in the phosphorylation levels of Collapsin Response Mediator Protein 2 (CRMP2) is involved in dopaminergic axon degeneration. In the present study, we report elevation of CRMP2 phosphorylation in dopaminergic neurons in SNc after challenge with the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a common model for PD. Genetic suppression of CRMP2 phosphorylation by mutation of the obligatory Cyclin-dependent kinase 5 (Cdk5)-targeted serine-522 site prevented axonal degradation in the nigrostriatal pathway of transgenic mice. As a result, the degree of MPTP-induced motor impairment in the rotarod test was suppressed. These results suggest that suppression of CRMP2 phosphorylation may be a novel therapeutic target for PD.",
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    AU - Hasegawa, Masaya

    AU - Nagai, Jun

    AU - Tonouchi, Aine

    AU - Masukawa, Daiki

    AU - Hensley, Kenneth

    AU - Goshima, Yoshio

    AU - Ohshima, Toshio

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    N2 - Parkinson's disease (PD) is a common neurodegenerative disorder characterized by slow and progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc). Levodopa (l-Dopa), the current main treatment for PD, supplies dopamine, but it does not prevent neurodegeneration. There is thus no promising remedy for PD. Recent in vitro study showed the increase in the phosphorylation levels of Collapsin Response Mediator Protein 2 (CRMP2) is involved in dopaminergic axon degeneration. In the present study, we report elevation of CRMP2 phosphorylation in dopaminergic neurons in SNc after challenge with the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a common model for PD. Genetic suppression of CRMP2 phosphorylation by mutation of the obligatory Cyclin-dependent kinase 5 (Cdk5)-targeted serine-522 site prevented axonal degradation in the nigrostriatal pathway of transgenic mice. As a result, the degree of MPTP-induced motor impairment in the rotarod test was suppressed. These results suggest that suppression of CRMP2 phosphorylation may be a novel therapeutic target for PD.

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