Inhibition of collapsin response mediator protein-2 phosphorylation ameliorates motor phenotype of ALS model mice expressing SOD1G93A

Yurika Numata-Uematsu, Shuji Wakatsuki, Seiichi Nagano, Megumi Shibata, Kazuhisa Sakai, Noritaka Ichinohe, Katsuhiko Mikoshiba, Toshio Ohshima, Naoya Yamashita, Yoshiro Goshima, Toshiyuki Araki

    Research output: Contribution to journalArticle

    4 Citations (Scopus)

    Abstract

    Amyotrophic lateral sclerosis (ALS) is an adult-onset neurological disease characterized by the selective degeneration of motor neurons leading to paralysis and immobility. Missense mutations in the gene coding for the Cu2+/Zn2+ superoxide dismutase 1 (SOD1) accounts for 15–20% of familial ALS, and mice overexpressing ALS-linked SOD1 mutants have been frequently used as an animal model for ALS. Degeneration of motor neurons in ALS progresses in a manner called “dying back”, in which the degeneration of synapses and axons precedes the loss of cell bodies. Phosphorylation of collapsin response mediator protein 2 (CRMP2) is implicated in the progression of neuronal/axonal degeneration of different etiologies. To evaluate the role of CRMP2 phosphorylation in ALS pathogenesis, we utilized CRMP2 S522A knock-in (CRMP2ki/ki) mice, in which the serine residue 522 was homozygously replaced with alanine and thereby making CRMP2 no longer phosphorylatable by CDK5 or GSK3B. We found that the CRMP2ki/ki/SOD1G93A mice showed delay in the progression of the motor phenotype compared to their SOD1G93-Tg littermates. Histological analysis revealed that the CRMP2ki/ki/SOD1G93A mice retained more intact axons and NMJs than their SOD1G93A-Tg littermates. These results suggest that the phosphorylation of CRMP2 may contribute to the axonal degeneration of motor neurons in ALS.

    Original languageEnglish
    JournalNeuroscience Research
    DOIs
    Publication statusAccepted/In press - 2018 Jan 1

    Fingerprint

    Amyotrophic Lateral Sclerosis
    Phosphorylation
    Phenotype
    Motor Neurons
    Axons
    Missense Mutation
    Paralysis
    Alanine
    Synapses
    Serine
    collapsin response mediator protein-2
    Animal Models
    Genes

    Keywords

    • ALS
    • Axonal degeneration
    • CRMP2
    • Neuromuscular junction

    ASJC Scopus subject areas

    • Neuroscience(all)

    Cite this

    Inhibition of collapsin response mediator protein-2 phosphorylation ameliorates motor phenotype of ALS model mice expressing SOD1G93A. / Numata-Uematsu, Yurika; Wakatsuki, Shuji; Nagano, Seiichi; Shibata, Megumi; Sakai, Kazuhisa; Ichinohe, Noritaka; Mikoshiba, Katsuhiko; Ohshima, Toshio; Yamashita, Naoya; Goshima, Yoshiro; Araki, Toshiyuki.

    In: Neuroscience Research, 01.01.2018.

    Research output: Contribution to journalArticle

    Numata-Uematsu, Y, Wakatsuki, S, Nagano, S, Shibata, M, Sakai, K, Ichinohe, N, Mikoshiba, K, Ohshima, T, Yamashita, N, Goshima, Y & Araki, T 2018, 'Inhibition of collapsin response mediator protein-2 phosphorylation ameliorates motor phenotype of ALS model mice expressing SOD1G93A', Neuroscience Research. https://doi.org/10.1016/j.neures.2018.08.016
    Numata-Uematsu, Yurika ; Wakatsuki, Shuji ; Nagano, Seiichi ; Shibata, Megumi ; Sakai, Kazuhisa ; Ichinohe, Noritaka ; Mikoshiba, Katsuhiko ; Ohshima, Toshio ; Yamashita, Naoya ; Goshima, Yoshiro ; Araki, Toshiyuki. / Inhibition of collapsin response mediator protein-2 phosphorylation ameliorates motor phenotype of ALS model mice expressing SOD1G93A. In: Neuroscience Research. 2018.
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    abstract = "Amyotrophic lateral sclerosis (ALS) is an adult-onset neurological disease characterized by the selective degeneration of motor neurons leading to paralysis and immobility. Missense mutations in the gene coding for the Cu2+/Zn2+ superoxide dismutase 1 (SOD1) accounts for 15–20{\%} of familial ALS, and mice overexpressing ALS-linked SOD1 mutants have been frequently used as an animal model for ALS. Degeneration of motor neurons in ALS progresses in a manner called “dying back”, in which the degeneration of synapses and axons precedes the loss of cell bodies. Phosphorylation of collapsin response mediator protein 2 (CRMP2) is implicated in the progression of neuronal/axonal degeneration of different etiologies. To evaluate the role of CRMP2 phosphorylation in ALS pathogenesis, we utilized CRMP2 S522A knock-in (CRMP2ki/ki) mice, in which the serine residue 522 was homozygously replaced with alanine and thereby making CRMP2 no longer phosphorylatable by CDK5 or GSK3B. We found that the CRMP2ki/ki/SOD1G93A mice showed delay in the progression of the motor phenotype compared to their SOD1G93-Tg littermates. Histological analysis revealed that the CRMP2ki/ki/SOD1G93A mice retained more intact axons and NMJs than their SOD1G93A-Tg littermates. These results suggest that the phosphorylation of CRMP2 may contribute to the axonal degeneration of motor neurons in ALS.",
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    AU - Numata-Uematsu, Yurika

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    AU - Nagano, Seiichi

    AU - Shibata, Megumi

    AU - Sakai, Kazuhisa

    AU - Ichinohe, Noritaka

    AU - Mikoshiba, Katsuhiko

    AU - Ohshima, Toshio

    AU - Yamashita, Naoya

    AU - Goshima, Yoshiro

    AU - Araki, Toshiyuki

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    N2 - Amyotrophic lateral sclerosis (ALS) is an adult-onset neurological disease characterized by the selective degeneration of motor neurons leading to paralysis and immobility. Missense mutations in the gene coding for the Cu2+/Zn2+ superoxide dismutase 1 (SOD1) accounts for 15–20% of familial ALS, and mice overexpressing ALS-linked SOD1 mutants have been frequently used as an animal model for ALS. Degeneration of motor neurons in ALS progresses in a manner called “dying back”, in which the degeneration of synapses and axons precedes the loss of cell bodies. Phosphorylation of collapsin response mediator protein 2 (CRMP2) is implicated in the progression of neuronal/axonal degeneration of different etiologies. To evaluate the role of CRMP2 phosphorylation in ALS pathogenesis, we utilized CRMP2 S522A knock-in (CRMP2ki/ki) mice, in which the serine residue 522 was homozygously replaced with alanine and thereby making CRMP2 no longer phosphorylatable by CDK5 or GSK3B. We found that the CRMP2ki/ki/SOD1G93A mice showed delay in the progression of the motor phenotype compared to their SOD1G93-Tg littermates. Histological analysis revealed that the CRMP2ki/ki/SOD1G93A mice retained more intact axons and NMJs than their SOD1G93A-Tg littermates. These results suggest that the phosphorylation of CRMP2 may contribute to the axonal degeneration of motor neurons in ALS.

    AB - Amyotrophic lateral sclerosis (ALS) is an adult-onset neurological disease characterized by the selective degeneration of motor neurons leading to paralysis and immobility. Missense mutations in the gene coding for the Cu2+/Zn2+ superoxide dismutase 1 (SOD1) accounts for 15–20% of familial ALS, and mice overexpressing ALS-linked SOD1 mutants have been frequently used as an animal model for ALS. Degeneration of motor neurons in ALS progresses in a manner called “dying back”, in which the degeneration of synapses and axons precedes the loss of cell bodies. Phosphorylation of collapsin response mediator protein 2 (CRMP2) is implicated in the progression of neuronal/axonal degeneration of different etiologies. To evaluate the role of CRMP2 phosphorylation in ALS pathogenesis, we utilized CRMP2 S522A knock-in (CRMP2ki/ki) mice, in which the serine residue 522 was homozygously replaced with alanine and thereby making CRMP2 no longer phosphorylatable by CDK5 or GSK3B. We found that the CRMP2ki/ki/SOD1G93A mice showed delay in the progression of the motor phenotype compared to their SOD1G93-Tg littermates. Histological analysis revealed that the CRMP2ki/ki/SOD1G93A mice retained more intact axons and NMJs than their SOD1G93A-Tg littermates. These results suggest that the phosphorylation of CRMP2 may contribute to the axonal degeneration of motor neurons in ALS.

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