DDAH1 Attenuates Parkinson's Disease Insults Possible via FOXO3 Mediated Pathway

摘要

Objective:Oxidative stress is one cardinal pathogenesis in Parkinson's disease that induces dopaminergic neuron loss in substantia nigra(SN). However, the related endogenous anti-oxidative defense system to protect against the stress still remains elusive. Dimethylarginine dimethylamine hydrolase 1(DDAH1), as a response factor, might be a protective player in various diseases. Herein, it is proposed that DDAH1 might alleviate PD insults through antioxidative stress. Methods:Plasma DDAH1 levels in PD patients were measured by ELISA. DDAH1 transgenic mice, DDAH1 general knockout mice, and C57 BL/6N wild-type mice were used to establish an MPTP-induced PD model. Results:Plasma DDAH1 levels were positively correlated with H-Y stage and MDS-UPDRS scores, respectively. After MPTP treatment, DDAH1 expression in the midbrain was significantly increased. Comparisons among the three mouse strains revealed that DDAH1 overexpression reduced MPTP-induced dopaminergic neuron loss, ameliorated neuronal injury in the SN, and attenuated motor deficits. Conclusion:DDAH1 exerts neuroprotective effects in MPTP-induced PD models, possibly via activation of the FOXO3/SOD2 antioxidative pathway, which in turn attenuates abnormally enhanced autophagy.

关键词

DDAH1 / Parkinson's disease / FOXO3 / autophagy