Dysfunction of microtubule has been implicated with neurodegenerations. Recently, I identified microtubule depolymerization and the accumulation of cytosolic dopamine and reactive oxygen species as a new mechanisms underlying rotenone-induced dopamine neuron death. It was hypothesized that vesicular dopamine is released to the cytosol when dopaminergic neurons are treated with rotenone in the model. However, the molecular factor that induces dopamine release from synaptic vesicles was not identified. Previously, I demonstrated the role of neuron specific isoform of c-Jun N-terminal kinase, JNK3 in pesticide-induced PD models. In this study, I investigated the mechanisms mediated by JNK3 in Rotenone (ROT)-induced dopaminergic neuron death. First, rotenone-induced JNK activation was attenuated by microtubule stablizer implicating that JNK is activated by microtubule destabilization or downstream factors in ROT-induced dopaminergic neuron death. Second, JNK3 inhibited VMAT2 activity. VMAT2 inhibition results in the increase of cytosolic dopamine, ROS and subsequent neuron death in ROT model. Furthermore, knockout of JNK3 prevented ROS increase and caspase activation in the dopaminergic neurons treated with ROT.
These results suggest that disrupting microtubule dynamics induces dopamine accumulation and JNK3 activation that mediates ROT-induced dopaminergic neuron death by inhibiting VMAT2 activity.