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

Acta Pharmacologica Sinica (2024)Cite this article

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.

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Fig. 1: Rg1 confers protection against psychological stress-induced Parkinson’s disease.
Fig. 2: Rg1 ameliorates dopaminergic neuron degeneration and αSyn accumulation.
Fig. 3: Rg1 reverses RTP801 upregulation in CSGS model.
Fig. 4: Rg1 promotes RTP801 degradation via the E3 ligase Parkin.
Fig. 5: RTP801 is a pivotal factor in stress-induced PD susceptibility and the therapeutic potential of Rg1.
Fig. 6: Rg1 mitigates RTP801-induced autophagic degradation impairment.
Fig. 7: Abnormal RTP801-TXNIP-ATP13A2 pathway was mitigated by Rg1 to rescue autolysosomal dysfunction.
Fig. 8: Ginsenoside Rg1 alleviates stress-exacerbated Parkinson’s disease by promoting RTP801 degradation.

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Acknowledgements

This study was 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).

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  1. These authors contributed equally: Sha-sha Wang, Ye Peng

Authors and Affiliations

  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

    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

  2. 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

  3. School of Pharmacy, Minzu University of China, Beijing, 100081, China

    Ye Peng

  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

    Ya-juan Tian & Wen-bin He

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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.

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Correspondence to Zhao Zhang, Shi-feng Chu or Nai-hong Chen.

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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 (2024). https://doi.org/10.1038/s41401-024-01374-w

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