Inhibition of collapsin response mediator protein-2 phosphorylation ameliorates motor phenotype of ALS model mice expressing SOD1G93A. (February 2019)

• Record Type: Journal Article
• Authors: Numata-Uematsu, Yurika; Wakatsuki, Shuji; Nagano, Seiichi; Shibata, Megumi; Sakai, Kazuhisa; Ichinohe, Noritaka; Mikoshiba, Katsuhiko; Ohshima, Toshio; Yamashita, Naoya; Goshima, Yoshiro; Araki, Toshiyuki
• Is Part Of: Neuroscience research. Volume 139(2019)
• Page Start: 63
• Page End: 68
• Publication Date: 2019-02
• Subjects: CRMP2 collapsin response mediator protein-2 -- ALS amyotrophic lateral sclerosis -- CDK5 cyclin dependent kinase 5 -- NMJ neuromuscular junction -- SOD1 superoxide dismutase 1 -- Tg transgenic -- ki knock in -- Sema3A semaphoren 3A -- GSK glycogen synthase kinase -- PB phosphate buffer -- BSA bovine serum albumin -- NRP1 neuropilin-1 -- TA tibialis anterior muscle; ALS -- CRMP2 -- Axonal degeneration -- Neuromuscular junction; Neurosciences -- Research -- Periodicals; Neurosciences -- Research -- Japan -- Periodicals; Neurology -- Periodicals; Neurosciences -- Periodicals; Neurosciences -- Recherche -- Périodiques; Neurosciences -- Recherche -- Japon -- Périodiques; Neurosciences -- Research; Japan; Periodicals; 612.8
• DOI: 10.1016/j.neures.2018.08.016
• Languages: English
• ISSNs: 0168-0102

Abstract

Highlights: Inhibition of CRMP2 phosphorylation delays progression of the motor symptoms of SOD1G93A-Tg mice. Inhibition of CRMP2 phosphorylation maintains the survival of motor axons in SOD1G93A-Tg mice. Inhibition of CRMP2 phosphorylation maintains innervation of NMJs in SOD1G93A-Tg mice. Phosphorylation of CRMP2 may promote dying back axonal degeneration in motor neurons in ALS. 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 Cu 2+ /Zn 2+ 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 (CRMP2 ki/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 CRMP2 ki/ki /SOD1 G93A mice showed delay in the progression of the motor phenotype compared to their SOD1 G93 -Tg littermates. Histological analysis revealed that the CRMP2 ki/ki /SOD1 G93A mice retained more intact axons and NMJs than their SOD1 G93A -Tg littermates. These results suggest that the phosphorylation of CRMP2 may contribute to the axonal degeneration of motor neurons in ALS.