Glutathione peroxidase 4 deficit-mediated fer⁃roptosis contributes to dopaminergic neuron degeneration under synucleinopathy  

作　　者：SUN Jie LU Dan-hua LI Kun LIN Xiao-min PAN Ming-hai GONG Hai-biao SUN Wan-yang WANG Meng LIANG Lei Kurihara Hiroshi LI Yi-fang DUAN Wen-jun ZHANG Li HE Rong-rong 

机构地区：[1]Guangdong Engineering Research Center of Chinese Medicine&Disease Susceptibility [2]International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education(MOE),College of Pharmacy [3]Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research,College of Pharmacy [4]School of Traditional Chinese Medicine [5]Key Laboratory of Central CNS Regeneration(Ministry of Education),Guangdong-Hong Kong-Macao Institute of CNS Regeneration,Jinan University,Guangzhou 510632,China

出　　处：《中国药理学与毒理学杂志》2021年第9期645-646,共2页Chinese Journal of Pharmacology and Toxicology

基　　金：National Key Research and Development Program of China(2017YFC1700404);Natural Science Foundation of China(81873209);Natural Science Foundation of China(U1801284);Natural Science Foundation of China(81903821);Natural Science Foundation of China(81973718);the Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program(2017BT01Y036);GDUPS(2019),Fun⁃damental Research Funds for the Central Univer⁃sities(21620448);Natural Science Foundation of Guangdong Province(2019A 1515010909);Nat⁃ural Science Foundation of Guangdong Prov⁃ince(2021A1515011297);Science and Tech⁃nology Program of Guangzhou(201903010062);Science and Technology Program of Guang⁃zhou(907158833068),and the Innovation Team Project of Guangdong Provincial Department of Education(2020KCXT D003)。

摘　　要：OBJECTIVE Intracellular aggre⁃gation ofα-synuclein(SNCA)is one of the core pathological features of neurodegenerative disor⁃ders including Parkinson disease,whilst the detailed mechanism for consequently neuron loss has not been fully illustrated.Since the altered phospholipid homeostasis has been suggested to play a role in synucleinopathy,this study aims to depict the fully-featured status of phospholip⁃ids and the targets reposingα-synuclein-related neurotoxicity.METHODS SNCAA53T transgenic mice were utilized as the model of Parkinson disease.Behavioral tests including pole test,rotarod test and gait analysis were conducted to assess the motor features of Parkinsonism.Tyro⁃sine hydroxylase were determined by immunohis⁃tochemistry.Glutathione,dopamine,3,4-dihy⁃droxyphenylacetic acid and homovanillic acid were determined by HPLC-ECD analysis.Assess⁃ment of lipid peroxidation included MDA assay and Liperfluo staining.Phospholipid-omics was analyzed based on LC-MS/MS.Investigation on mechanism was relied on Western blotting and qPCR assay.The injection of AAV into midbrain was achieved by ultra-micro injection pump to obtain the target genotype.RESULTS SNCAA53T transgenic mice displayed progres⁃sively deteriorated motor coordination functions and the mechanisms were related with lipid per⁃oxidation and ferroptosis,which might help to explain the parkinsonism.These hydroperoxides were observed on plasm membrane and were further characterized by LC-MS/MS-based phos⁃pholipid-omics analysis.α-synucleinA53T trans⁃genic mice displayed distinct patterns of phos⁃pholipid peroxidation in midbrain regions com⁃pared to wild type littermates.Among different subtypes of oxidized phospholipids,oxidative phosphatidylcholine(PC-ox)was more promi⁃nently elevated.Phospholipid peroxidation is believed as a biomarker of ferroptosis,which is largely a specialized death program caused by insufficiency of glutathione peroxidase-4(GPX4),the only known enzyme that can reduce lipid hydroperoxides within biolo

关 键 词：Parkinson disease ferroptosis glutathione peroxidase-4 phospholipid-omics Α-SYNUCLEIN 

分 类 号：R741.02[医药卫生—神经病学与精神病学]