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1.
Genes Cells ; 24(1): 31-40, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30375127

RESUMO

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.


Assuntos
Peptídeos e Proteínas de Sinalização Intercelular/genética , Proteínas do Tecido Nervoso/genética , Doença de Parkinson/genética , Supressão Genética , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/análogos & derivados , Animais , Modelos Animais de Doenças , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microglia/metabolismo , Microglia/patologia , Atividade Motora , Neostriado/patologia , Degeneração Neural/patologia , Doença de Parkinson/patologia , Doença de Parkinson/fisiopatologia , Fosforilação , Substância Negra/patologia
2.
J Neurochem ; 137(5): 795-805, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26991935

RESUMO

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.


Assuntos
Modelos Animais de Doenças , Neurônios Dopaminérgicos/metabolismo , Intoxicação por MPTP/metabolismo , Proteínas do Tecido Nervoso/deficiência , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/farmacologia , Animais , Morte Celular/efeitos dos fármacos , Morte Celular/fisiologia , Neurônios Dopaminérgicos/patologia , Intoxicação por MPTP/patologia , Masculino , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout
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