The Essential Role of Drp1 and Its Regulation by S-Nitrosylation of Parkin in Dopaminergic Neurodegeneration: Implications for Parkinson's Disease.
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.



We demonstrated that nitric oxide (NO) was overproduced on 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. In addition, 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.



We first showed that SNO-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.



Our results provide a molecular explanation for the contribution of Drp1 to the pathogenesis of sporadic PD. These findings indicate that the SNO-Parkin pathway may be a novel therapeutic target to treat PD. Antioxid. Redox Signal. 25, 609-622.
MOE Key Laboratory of Laser Life Science & Institute of Laser Life Science, College of Biophotonics, South China Normal University , Guangzhou, China .
Zhenzhen
Z
Zhang
MOE Key Laboratory of Laser Life Science & Institute of Laser Life Science, College of Biophotonics, South China Normal University , Guangzhou, China .
Lei
L
Liu
MOE Key Laboratory of Laser Life Science & Institute of Laser Life Science, College of Biophotonics, South China Normal University , Guangzhou, China .
XiaoXiao
X
Jiang
MOE Key Laboratory of Laser Life Science & Institute of Laser Life Science, College of Biophotonics, South China Normal University , Guangzhou, China .
ShaoDong
S
Zhai
MOE Key Laboratory of Laser Life Science & Institute of Laser Life Science, College of Biophotonics, South China Normal University , Guangzhou, China .
Da
D
Xing
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000009:adverse effects; D000818:Animals; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000378:metabolism / Q000473:pathology; D034281:Dynamins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000235:genetics / Q000473:pathology; D063154:Mitochondrial Dynamics / Q000235:genetics; D009410:Nerve Degeneration / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; C486391:Dnm1l protein, mouse; D034281:Dynamins; D004298:Dopamine