ROCK1/Drp1-mediated aberrant mitochondrial fission is crucial for dopaminergic nerve cell apoptosis

Dopamine deficiency caused by apoptosis of the dopaminergic nerve cells in the midbrain substantia nigra is the main pathological basis of Parkinson9s disease (PD). Recent research has shown that dynamin-related protein 1 (Drp1)-mediated aberrant mitochondrial fission plays an important role in dopaminergic nerve cell apoptosis. However, the upstream regulatory mechanism remains unclear. Our study shows that knockdown of Drp1 blocked aberrant mitochondrial fission and dopaminergic nerve cell apoptosis. Importantly, we found that ROCK1 was activated in an MPP+-induced PD cell model and that ROCK1 knockdown and the specific ROCK1 activation inhibitor Y-27632 blocked Drp1-mediated aberrant mitochondrial fission and apoptosis of dopaminergic nerve cell through suppression of Drp1 dephosphorylation/activation. Our in vivo study confirmed that Y-27632 significantly improved symptoms of a PD mouse model through inhibition of Drp1-mediated aberrant mitochondrial fission and apoptosis of dopaminergic nerve cell. Collectively, Our study suggests an important molecular mechanism of PD pathogenesis involving ROCK1-regulated dopaminergic nerve cell apoptosis via activation of Drp1-induced aberrant mitochondrial fission.