Ginsenoside Rg1 ameliorates stress-exacerbated Parkinson’s disease in mice by eliminating RTP801 andα-synuclein autophagic degradation obstacle  

作　　者：Sha-sha Wang Ye Peng Ping-long Fan Jun-rui Ye Wen-yu Ma Qing-lin Wu Hong-yun Wang Ya-juan Tian Wen-bin He Xu Yan Zhao Zhang Shi-feng Chu Nai-hong Chen 

机构地区：[1]State Key Laboratory of Bioactive Substances and Functions of Natural Medicines,Institute of Materia Medica&Neuroscience Center,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing,100050,China [2]Science and Technology Innovation Center,Guangzhou University of Chinese Medicine,Guangzhou,510405,China [3]School of Pharmacy,Minzu University of China,Beijing,100081,China [4]Shanxi Key Laboratory of Chinese Medicine Encephalopathy,National International Joint Research Center for Molecular Chinese Medicine,Shanxi University of Chinese Medicine,Taiyuan,030024,China

出　　处：《Acta Pharmacologica Sinica》2025年第2期308-325,共18页中国药理学报(英文版)

基　　金：supported by the National Key R&D Program of China(2022YFC3500300);the National Natural Science Foundation of China(82130109,81973499);the CAMS Innovation Fund for Medical Sciences(CIFMS)(2021-I2M-1-020).

摘　　要：Emerging evidence shows that psychological stress promotes the progression of Parkinson’s disease(PD)and the onset of dyskinesia in non-PD individuals,highlighting a potential avenue for therapeutic intervention.We previously reported that chronic restraint-induced psychological stress precipitated the onset of parkinsonism in 10-month-old transgenic mice expressing mutant humanα-synuclein(αSyn)(hαSyn A53T).We refer to these as chronic stress-genetic susceptibility(CSGS)PD model mice.In this study we investigated whether ginsenoside Rg1,a principal compound in ginseng notable for soothing the mind,could alleviate PD deterioration induced by psychological stress.Ten-month-old transgenic hαSyn A53T mice were subjected to 4 weeks’restraint stress to simulate chronic stress conditions that worsen PD,meanwhile the mice were treated with Rg1(40 mg·kg^(−1)·d^(−1),i.g.),and followed by functional magnetic resonance imaging(fMRI)and a variety of neurobehavioral tests.We showed that treatment with Rg1 significantly alleviated both motor and non-motor symptoms associated with PD.Functional MRI revealed that Rg1 treatment enhanced connectivity between brain regions implicated in PD,and in vivo multi-channel electrophysiological assay showed improvements in dyskinesia-related electrical activity.In addition,Rg1 treatment significantly attenuated the degeneration of dopaminergic neurons and reduced the pathological aggregation ofαSyn in the striatum and SNc.We revealed that Rg1 treatment selectively reduced the level of the stress-sensitive protein RTP801 in SNc under chronic stress conditions,without impacting the acute stress response.HPLC-MS/MS analysis coupled with site-directed mutation showed that Rg1 promoted the ubiquitination and subsequent degradation of RTP801 at residues K188 and K218,a process mediated by the Parkin RING2 domain.UtilizingαSyn A53T+;RTP801−/−mice,we confirmed the critical role of RTP801 in stress-aggravated PD and its necessity for Rg1’s protective effects.Moreover,Rg1 allevia

关 键 词：Parkinson's disease(PD) psychological stress RG1 RTP801 a-Synuclein AUTOPHAGY 

分 类 号：R28[医药卫生—中药学]