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ABSTRACT 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 human α-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 of αSyn 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. Utilizing αSyn A53T+; RTP801−/− mice, we confirmed the critical role of RTP801 in stress-aggravated PD and its necessity for Rg1’s protective effects. Moreover, Rg1

alleviated obstacles in αSyn autophagic degradation by ameliorating the RTP801-TXNIP-mediated deficiency of ATP13A2. Collectively, our results suggest that ginsenoside Rg1 holds promise as a

therapeutic choice for treating PD-sensitive individuals who especially experience high levels of stress and self-imposed expectations. Access through your institution Buy or subscribe This

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INDUCES DEPRESSION-LIKE BEHAVIORS AND PARKINSONISM VIA UPREGULATING Α-SYNUCLEIN Article Open access 28 May 2025 BNIP3L/NIX-MEDIATED MITOPHAGY ALLEVIATES PASSIVE STRESS-COPING BEHAVIORS

INDUCED BY TUMOR NECROSIS FACTOR-Α Article 13 March 2023 GINSENOSIDE RG1 ALLEVIATES CHRONIC STRESS-INDUCED DEPRESSION IN RATS BY TARGETING CX43-YAP AXIS Article 07 March 2025 REFERENCES *

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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). AUTHOR INFORMATION Author notes * These authors contributed equally: Sha-sha Wang, Ye Peng AUTHORS AND AFFILIATIONS * 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 Sha-sha

Wang, Ye Peng, Ping-long Fan, Jun-rui Ye, Wen-yu Ma, Qing-lin Wu, Hong-yun Wang, Xu Yan, Zhao Zhang, Shi-feng Chu & Nai-hong Chen * Science and Technology Innovation Center, Guangzhou

University of Chinese Medicine, Guangzhou, 510405, China Sha-sha Wang, Ping-long Fan, Wen-yu Ma, Qing-lin Wu & Nai-hong Chen * School of Pharmacy, Minzu University of China, Beijing,

100081, China Ye Peng * Shanxi Key Laboratory of Chinese Medicine Encephalopathy, National International Joint Research Center for Molecular Chinese Medicine, Shanxi University of Chinese

Medicine, Taiyuan, 030024, China Ya-juan Tian & Wen-bin He Authors * Sha-sha Wang View author publications You can also search for this author inPubMed Google Scholar * Ye Peng View

author publications You can also search for this author inPubMed Google Scholar * Ping-long Fan View author publications You can also search for this author inPubMed Google Scholar * Jun-rui

Ye View author publications You can also search for this author inPubMed Google Scholar * Wen-yu Ma View author publications You can also search for this author inPubMed Google Scholar *

Qing-lin Wu View author publications You can also search for this author inPubMed Google Scholar * Hong-yun Wang View author publications You can also search for this author inPubMed Google

Scholar * Ya-juan Tian View author publications You can also search for this author inPubMed Google Scholar * Wen-bin He View author publications You can also search for this author inPubMed

 Google Scholar * Xu Yan View author publications You can also search for this author inPubMed Google Scholar * Zhao Zhang View author publications You can also search for this author

inPubMed Google Scholar * Shi-feng Chu View author publications You can also search for this author inPubMed Google Scholar * Nai-hong Chen View author publications You can also search for

this author inPubMed Google Scholar CONTRIBUTIONS NHC, ZZ, SFC, and SSW conceived and designed the study. SSW, YP, PLF, JRY, WYM and XY performed the experiments. JRY, QLW, HYW and YJT

participated in data analysis. SSW and ZZ wrote the manuscript. NHC, SFC, ZZ, YP and WBH revised the manuscript. All the authors have read and approved the final version of the manuscript.

CORRESPONDING AUTHORS Correspondence to Zhao Zhang, Shi-feng Chu or Nai-hong Chen. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no competing interests. SUPPLEMENTARY

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publishing agreement and applicable law. Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Wang, Ss., Peng, Y., Fan, Pl. _et al._ Ginsenoside Rg1 ameliorates stress-exacerbated

Parkinson’s disease in mice by eliminating RTP801 and α-synuclein autophagic degradation obstacle. _Acta Pharmacol Sin_ 46, 308–325 (2025). https://doi.org/10.1038/s41401-024-01374-w

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Provided by the Springer Nature SharedIt content-sharing initiative KEYWORDS * Parkinson’s disease (PD) * psychological stress * Rg1 * RTP801 * α-Synuclein * autophagy