title: Loss of collapsin response mediator protein 4 suppresses dopaminergic neuron death in an 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced mouse model of Parkinson's disease.
abstract: Parkinson's disease (PD) is a progressive neurodegenerative disorder that is characterized by the selective loss of dopaminergic neurons in the substantia nigra pars compacta (SNc). Several lines of evidence suggest that neurodegeneration in PD is accelerated by a vicious cycle in which apoptosis in dopaminergic neurons triggers the activation of microglia and harmful inflammatory processes that further amplify neuronal death. Recently, we demonstrated that the deletion of collapsin response mediator protein 4 (CRMP4) suppresses inflammatory responses and cell death in a mouse model of spinal cord injury, leading to improved functional recovery. We thus hypothesized that Crmp4-/- mice may have limited inflammatory responses and a decrease in the loss of SNc dopaminergic neurons in an 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse model. We observed CRMP4 expression in neurons, astrocytes, and microglia/macrophages following the injection of 25 mg/kg MPTP. We compared the number of dopaminergic neurons and the inflammatory response in SNc between Crmp4+/+ and Crmp4-/- mice after MPTP injection. Limited loss of SNc dopaminergic neurons and decreased activations of microglia and astrocytes were observed in Crmp4-/- mice. These results suggest that CRMP4 is a novel therapeutic target in the treatment of PD patients. We demonstrated that genetic CRMP4 deletion delays a vicious cycle of inflammation and neurodegeneration in a Parkinson's disease mouse model. MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) injection to wild-type mice induces collapsin response mediator protein 4 (CRMP4) up-regulation in neurons, astrocytes, and microglia. CRMP4-deficient mice show reduced inflammation and suppressed dopaminergic neuronal death after MPTP injection. These findings suggest that CRMP4 deletion may be a new therapeutic strategy against Parkinson's diseases.
authors.affiliation: Department of Life Science and Medical Bioscience, Graduate School of Advanced Science and Engineering, Waseda University, Tokyo, Japan.
authors.forename: Aine
authors.initials: A
authors.lastname: Tonouchi
authors.affiliation: Department of Life Science and Medical Bioscience, Graduate School of Advanced Science and Engineering, Waseda University, Tokyo, Japan.|Japan Society for the Promotion of Science, Tokyo, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Nagai
authors.affiliation: Department of Life Science and Medical Bioscience, Graduate School of Advanced Science and Engineering, Waseda University, Tokyo, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Togashi
authors.affiliation: Department of Molecular Pharmacology and Neurobiology, Graduate School of Medicine, Yokohama City University, Yokohama, Japan.
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Goshima
authors.affiliation: Department of Life Science and Medical Bioscience, Graduate School of Advanced Science and Engineering, Waseda University, Tokyo, Japan.
authors.forename: Toshio
authors.initials: T
authors.lastname: Ohshima
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology; D000818:Animals; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000378:metabolism* / Q000473:pathology; D020267:MPTP Poisoning / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000172:deficiency*
chemical_list: C526904:Dpysl3 protein, mouse; D009419:Nerve Tissue Proteins; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
keywords: Parkinson's disease; dopaminergic neuron; inflammation; microglia