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 journalArticlepeer-review

10 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
Pages (from-to)63-68
Number of pages6
JournalNeuroscience Research
Volume139
DOIs
Publication statusPublished - 2019 Feb

Keywords

  • ALS
  • Axonal degeneration
  • CRMP2
  • Neuromuscular junction

ASJC Scopus subject areas

  • Neuroscience(all)

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