Gene transfer of the JNK interacting protein-1 protects dopaminergic neurons in the MPTP model of Parkinson's disease

Increasing evidence suggests that apoptosis may be the underlying cell deat h mechanism in the selective loss of dopaminergic neurons in Parkinson's di sease. Because the inhibition of caspases provides only partial protection in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/1-methyl-4-phenylpyridi nium (MPTP/MPP+) model of Parkinson's disease, we investigated the role of the proapoptotic c-Jun N-terminal kinase (JNK) signaling cascade in SH-SY5Y human neuroblastoma cells in vitro and in mice in vivo. MPTP/MPP+ led to t he sequential phosphorylation and activation of JNK kinase (MKK4), INK, and c-Jun, the activation of caspases, and apoptosis. In mice, adenoviral gene transfer of the INK binding domain of JNK-interacting protein-1 (a scaffol d protein and inhibitor of INK) inhibited this cascade downstream of MKK4 p hosphorylation, blocked JNK, c-Jun, and caspase activation, the death of do paminergic neurons, and the loss of catecholamines in the striatum. Further more, the gene transfer resulted in behavioral benefit. Therefore, inhibiti on of the INK pathway offers a new treatment strategy for Parkinson's disea se that blocks the death signaling pathway upstream of the execution of apo ptosis in dopaminergic neurons, providing a therapeutic advantage over the direct inhibition of caspases.