Membrane phospholipid peroxidation promotes loss of dopaminergic neurons in psychological stress-induced Parkinson's disease susceptibility.

Autor: Lin XM; Guangdong Engineering Research Center of Chinese Medicine & Disease Susceptibility/International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE)/Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research/The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, China., Pan MH; Guangdong Engineering Research Center of Chinese Medicine & Disease Susceptibility/International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE)/Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research/The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, China., Sun J; Guangdong Engineering Research Center of Chinese Medicine & Disease Susceptibility/International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE)/Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research/The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, China., Wang M; Guangdong Engineering Research Center of Chinese Medicine & Disease Susceptibility/International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE)/Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research/The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, China., Huang ZH; Guangdong Engineering Research Center of Chinese Medicine & Disease Susceptibility/International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE)/Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research/The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, China., Wang G; Innovation Center of Nursing Research, Nursing Key Laboratory of Sichuan Province, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu, China., Wang R; School of Chinese Materia Medica and Yunnan Key Laboratory of Southern Medicinal Utilization, Yunnan University of Chinese Medicine, Kunming, China., Gong HB; Guangdong Engineering Research Center of Chinese Medicine & Disease Susceptibility/International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE)/Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research/The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, China., Huang RT; State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China., Huang F; School of Chinese Materia Medica and Yunnan Key Laboratory of Southern Medicinal Utilization, Yunnan University of Chinese Medicine, Kunming, China., Sun WY; Guangdong Engineering Research Center of Chinese Medicine & Disease Susceptibility/International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE)/Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research/The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, China., Liu HZ; Guangdong Engineering Research Center of Chinese Medicine & Disease Susceptibility/International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE)/Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research/The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, China., Kurihara H; Guangdong Engineering Research Center of Chinese Medicine & Disease Susceptibility/International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE)/Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research/The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, China., Li YF; Guangdong Engineering Research Center of Chinese Medicine & Disease Susceptibility/International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE)/Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research/The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, China., Duan WJ; Guangdong Engineering Research Center of Chinese Medicine & Disease Susceptibility/International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE)/Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research/The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, China., He RR; Guangdong Engineering Research Center of Chinese Medicine & Disease Susceptibility/International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE)/Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research/The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, China.; School of Chinese Materia Medica and Yunnan Key Laboratory of Southern Medicinal Utilization, Yunnan University of Chinese Medicine, Kunming, China.; State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China.
Jazyk: angličtina
Zdroj: Aging cell [Aging Cell] 2023 Oct; Vol. 22 (10), pp. e13970. Date of Electronic Publication: 2023 Aug 25.
DOI: 10.1111/acel.13970
Abstrakt: Parkinson's disease (PD) is a neurodegenerative disorder associated with α-synuclein aggregation and dopaminergic neuron loss in the midbrain. There is evidence that psychological stress promotes PD progression by enhancing glucocorticoids-related oxidative damage, however, the mechanisms involved are unknown. The present study demonstrated that plasma membrane phospholipid peroxides, as determined by phospholipidomics, triggered ferroptosis in dopaminergic neurons, which in turn contributed to stress exacerbated PD-like motor disorder in mice overexpressing mutant human α-synuclein. Using hormonomics, we identified that stress stimulated corticosteroid release and promoted 15-lipoxygenase-1 (ALOX15)-mediated phospholipid peroxidation. ALOX15 was upregulated by α-synuclein overexpression and acted as a fundamental risk factor in the development of chronic stress-induced parkinsonism and neurodegeneration. Further, we demonstrated the mechanism by which corticosteroids activated the PKC pathway and induced phosphatidylethanolamine-binding protein-1 (PEBP1) to form a complex with ALOX15, thereby facilitating ALOX15 to locate on the plasma membrane phospholipids. A natural product isolated from herbs, leonurine, was screened with activities of inhibiting the ALOX15/PEBP1 interaction and thereby attenuating membrane phospholipid peroxidation. Collectively, our findings demonstrate that stress increases the susceptibility of PD by driving membrane lipid peroxidation of dopaminergic neurons and suggest the ALOX15/PEBP1 complex as a potential intervention target.
(© 2023 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)
Databáze: MEDLINE
Externí odkaz:
Nepřihlášeným uživatelům se plný text nezobrazuje