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. (18th November 2018)

• Record Type: Journal Article
• Authors: Togashi, Kentaro; Hasegawa, Masaya; Nagai, Jun; Tonouchi, Aine; Masukawa, Daiki; Hensley, Kenneth; Goshima, Yoshio; Ohshima, Toshio
• Is Part Of: Genes to cells. Volume 24:Number 1(2019)
• Page Start: 31
• Page End: 40
• Publication Date: 2018-11-18
• Subjects: CRMP2 phosphorylation -- dopaminergic neuron -- Parkinson's disease; Cytogenetics -- Periodicals; Cells -- Mechanical properties -- Periodicals; Molecular genetics -- Periodicals; Genes -- Periodicals; Molecular biology -- Periodicals; Cytology -- Periodicals; Biomechanics -- Periodicals; 571.6
• DOI: 10.1111/gtc.12651
• Languages: English
• ISSNs: 1356-9597

Abstract

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. Abstract : Enhanced level of CRMP2 phosphorylation at S522 is observed in SNc dopaminergic neurons of a MPTP mouse model of Parkinson's disease (PD). Genetic inhibition of CRMP2 phosphorylation (Crmp2 knock‐in) suppresses the reduction of striatal TH protein level and motor impairment in the PD mouse model.