Targeting Mitochondrial Complex I Deficiency in MPP + /MPTP-induced Parkinson's Disease Cell Culture and Mouse Models by Transducing Yeast NDI1 Gene.

Autor: Li H; Key Laboratory of Laboratory Medicine, Ministry of Education, Wenzhou Key Laboratory of Cancer Pathogenesis and Translation, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Chashan University Town, Northern Zhongshan Road, Wenzhou, 325035, China. lhz@wmu.edu.cn., Zhang J; Department of Pathology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, China., Shen Y; Key Laboratory of Laboratory Medicine, Ministry of Education, Wenzhou Key Laboratory of Cancer Pathogenesis and Translation, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Chashan University Town, Northern Zhongshan Road, Wenzhou, 325035, China., Ye Y; Key Laboratory of Laboratory Medicine, Ministry of Education, Wenzhou Key Laboratory of Cancer Pathogenesis and Translation, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Chashan University Town, Northern Zhongshan Road, Wenzhou, 325035, China., Jiang Q; Key Laboratory of Laboratory Medicine, Ministry of Education, Wenzhou Key Laboratory of Cancer Pathogenesis and Translation, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Chashan University Town, Northern Zhongshan Road, Wenzhou, 325035, China., Chen L; Key Laboratory of Laboratory Medicine, Ministry of Education, Wenzhou Key Laboratory of Cancer Pathogenesis and Translation, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Chashan University Town, Northern Zhongshan Road, Wenzhou, 325035, China., Sun B; Department of Pathology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, China., Chen Z; Key Laboratory of Laboratory Medicine, Ministry of Education, Wenzhou Key Laboratory of Cancer Pathogenesis and Translation, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Chashan University Town, Northern Zhongshan Road, Wenzhou, 325035, China., Shen L; Department of Internal Neurology, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China., Fang H; Key Laboratory of Laboratory Medicine, Ministry of Education, Wenzhou Key Laboratory of Cancer Pathogenesis and Translation, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Chashan University Town, Northern Zhongshan Road, Wenzhou, 325035, China., Yang J; Key Laboratory of Laboratory Medicine, Ministry of Education, Wenzhou Key Laboratory of Cancer Pathogenesis and Translation, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Chashan University Town, Northern Zhongshan Road, Wenzhou, 325035, China. yjf@wmu.edu.cn., Gu H; Key Laboratory of Laboratory Medicine, Ministry of Education, Wenzhou Key Laboratory of Cancer Pathogenesis and Translation, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Chashan University Town, Northern Zhongshan Road, Wenzhou, 325035, China. haihuagu@wmu.edu.cn.
Jazyk: angličtina
Zdroj: Biological procedures online [Biol Proced Online] 2024 Apr 09; Vol. 26 (1), pp. 9. Date of Electronic Publication: 2024 Apr 09.
DOI: 10.1186/s12575-024-00236-3
Abstrakt: Background: MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), original found in synthetic heroin, causes Parkinson's disease (PD) in human through its metabolite MPP + by inhibiting complex I of mitochondrial respiratory chain in dopaminergic neurons. This study explored whether yeast internal NADH-quinone oxidoreductase (NDI1) has therapeutic effects in MPTP- induced PD models by functionally compensating for the impaired complex I. MPP + -treated SH-SY5Y cells and MPTP-treated mice were used as the PD cell culture and mouse models respectively. The recombinant NDI1 lentivirus was transduced into SH-SY5Y cells, or the recombinant NDI1 adeno-associated virus (rAAV5-NDI1) was injected into substantia nigra pars compacta (SNpc) of mice.
Results: The study in vitro showed NDI1 prevented MPP + -induced change in cell morphology and decreased cell viability, mitochondrial coupling efficiency, complex I-dependent oxygen consumption, and mitochondria-derived ATP. The study in vivo revealed that rAAV-NDI1 injection significantly improved the motor ability and exploration behavior of MPTP-induced PD mice. Accordingly, NDI1 notably improved dopaminergic neuron survival, reduced the inflammatory response, and significantly increased the dopamine content in striatum and complex I activity in substantia nigra.
Conclusions: NDI1 compensates for the defective complex I in MPP + /MPTP-induced models, and vastly alleviates MPTP-induced toxic effect on dopaminergic neurons. Our study may provide a basis for gene therapy of sporadic PD with defective complex I caused by MPTP-like substance.
(© 2024. The Author(s).)
Databáze: MEDLINE
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