The essential role of Drp1 and its regulation in PD

What is it about?

Aims: Dysfunctional regulation of mitochondrial dynamics, which switches the balance to fission, is involved in neurodegeneration in Parkinson’s disease (PD). Dynamin-related protein-1 (Drp1), a key regulator of mitochondrial fission, has been attributed recently to such neurodegeneration in PD. However, the machinery that connects Drp1 to the pathophysiology of PD is unclear. Results: We demonstrated that nitric oxide (NO) was overproduced upon 1-methyl-4-phenylpyridinium ion (MPP+) treatment, which subsequently engendered S-nitrosylation of Parkin (SNO-Parkin), and thus decreased the interaction with Drp1, leading to elevated Drp1 expression. Consistent with this, Drp1 was elevated in the ventral midbrain of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated PD mouse models, a region usually affected by PD. Concomitantly, in a mouse model of MPTP-induced PD, both SNO-Parkin and Drp1 levels were increased, whereas no significant difference in SNO-Drp1 protein levels were found in these mice. Additionally, NO stress, induced by MPP+ , triggered the phosphorylation of Drp1 Ser616 and caused its subsequent recruitment to the mitochondria. These events create a death-prone environment that contributes to the loss of dopaminergic neurons. Innovation: We first showed that S-nitrosylation of Parkin reduced its ability as a suppressor of Drp1 expression, leading to upregulation of Drp1 in neurotoxin-based PD models, in vitro and in vivo. Conclusion: Our results provide a molecular explanation for the contribution of Drp1 to the pathogenesis of sporadic PD. These findings indicate that SNO-Parkin pathway may be a novel therapeutic target to treat PD.

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Why is it important?

We first showed that S-nitrosylation of Parkin reduced its ability as a suppressor of dynamin-related protein-1 (Drp1) expression, leading to upregulation of Drp1 in neurotoxin-based Parkinson’s disease (PD) models, in vitro and in vivo. Drp1 appears directly pertinent to PD in that its expression is selectively elevated in susceptible neurons in MPTP-induced PD mouse models. Our data provide a molecular explanation for the contribution of Drp1 to PD pathogenesis. The discovery of NO signaling links MPP+ neurotoxicity to the malfunction in mitochondrial dynamics affords an opportunity to develop novel therapeutic strategy for sporadic PD.

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