c-Jun/Bim Upregulation in Dopaminergic Neurons Promotes Neurodegeneration in the MPTP Mouse Model of Parkinson's Disease.

Parkinson's disease (PD) is a common neurodegenerative disease that is characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). The proapoptotic BH3-only protein Bim has been reported to be involved in dopaminergic neurodegeneration of experimental PD. However, an in situ expression profile of Bim in PD has not been performed, and the cell types of which Bim accounts for PD pathogenesis is unclear. Here, we report with in situ observations that Bim is transcriptionally induced in the dopaminergic neurons of the SNpc in 1-methyl-4-pheny-1,2,3,6-tetrahydropyridine (MPTP)-treated mice. To investigate the precise role of Bim in the dopaminergic neurons in parkinsonian neuronal death, we obtained dopaminergic neuron-specific Bim null (Bim△Dat) mice. Bim△Dat mice are shown to be resistant to MPTP-induced neurotoxicity, confirming that the induction of Bim in dopaminergic neurons is responsible for parkinsonian neurodegeneration. Furthermore, we demonstrated with dopaminergic neuron-specific c-Jun knockout (c-Jun△Dat) that the transcriptional upregulation of Bim of nigral dopaminergic neurons was c-Jun-dependent and further validated the detrimental role of c-Jun in dopaminergic neurodegeneration. Together, these data specify that c-Jun-mediated Bim upregulation in nigral dopaminergic neurons contributes to parkinsonian neurodegeneration.