ROCK1 induces dopaminergic nerve cell apoptosis via the activation of Drp1-mediated aberrant mitochondrial fission in Parkinson’s disease

Dopamine deficiency is mainly caused by apoptosis of dopaminergic nerve cells in the substantia nigra of the midbrain and the striatum and is an important pathologic basis of Parkinson’s disease (PD). Recent research has shown that dynamin-related protein 1 (Drp1)-mediated aberrant mitochondrial fission plays a crucial role in dopaminergic nerve cell apoptosis. However, the upstream regulatory mechanism remains unclear. Our study showed that Drp1 knockdown inhibited aberrant mitochondrial fission and 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 cells by suppressing Drp1 dephosphorylation/activation. Our in vivo study confirmed that Y-27632 significantly improved symptoms in a PD mouse model by inhibiting Drp1-mediated aberrant mitochondrial fission and apoptosis. Collectively, our findings suggest an important molecular mechanism of PD pathogenesis involving ROCK1-regulated dopaminergic nerve cell apoptosis via the activation of Drp1-induced aberrant mitochondrial fission. Researchers in China have revealed how a protein molecule plays an early part in the molecular steps that can lead to Parkinson’s disease, which is caused by the death of nerve cells that make the neurotransmitter dopamine. Disruption of mitochondria, the energy-generating bodies inside cells, was already known to lead to the death of dopamine-producing cells. Rong Zhang, Guobing Li and colleagues at The Second Affiliated Hospital of Army Medical University in Chongqing, China traced the chain of cause and effect back to a protein called ROCK-1. Using a mouse model of Parkinson’s disease, they found that ROCK-1 activates another protein previously shown to trigger the disruption of mitochondria. ROCK-1’s early role in the sequence might make it a suitable target for treatment using drugs that inhibit its activity.