人参皂苷Rg1通过消除RTP801和α-突触核蛋白自噬降解障碍,改善小鼠因应激而加重的帕金森病。

IF 6.9 1区 医学 Q1 CHEMISTRY, MULTIDISCIPLINARY Acta Pharmacologica Sinica Pub Date : 2024-09-03 DOI:10.1038/s41401-024-01374-w
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
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引用次数: 0

摘要

新的证据表明,心理压力会促进帕金森病(PD)的进展和非帕金森病患者运动障碍的发生,这为治疗干预提供了潜在的途径。我们以前曾报道过,在表达突变型人类α-突触核蛋白(αSyn)(hαSyn A53T)的10月龄转基因小鼠中,慢性束缚诱导的心理应激会诱发帕金森病。我们将这些小鼠称为慢性应激-遗传易感性(CSGS)PD 模型小鼠。在这项研究中,我们探讨了人参皂苷 Rg1(人参中一种以舒缓精神而著称的主要化合物)是否能缓解心理压力引起的帕金森病恶化。我们对10个月大的转基因hαSyn A53T小鼠进行了4周的束缚应激,以模拟导致帕金森病恶化的慢性应激条件,同时用Rg1(40 mg- kg-1 -d-1,i.g.)治疗小鼠,并进行了功能磁共振成像(fMRI)和各种神经行为测试。我们的研究表明,Rg1能明显缓解与帕金森病相关的运动和非运动症状。功能磁共振成像(Functional MRI)显示,Rg1治疗增强了与帕金森病有关联的脑区之间的连通性,体内多通道电生理检测显示,运动障碍相关的电活动有所改善。此外,Rg1治疗还能显著减轻多巴胺能神经元的变性,减少纹状体和SNc中αSyn的病理性聚集。我们发现,在慢性应激条件下,Rg1能选择性地降低SNc中应激敏感蛋白RTP801的水平,而不影响急性应激反应。HPLC-MS/MS分析和定点突变显示,Rg1促进了RTP801在残基K188和K218处的泛素化和随后的降解,这一过程由Parkin RING2结构域介导。利用αSyn A53T+; RTP801-/-小鼠,我们证实了RTP801在应激加重的帕金森病中的关键作用及其对Rg1保护作用的必要性。此外,Rg1通过改善RTP801-TXNIP介导的ATP13A2缺陷,缓解了αSyn自噬降解的障碍。总之,我们的研究结果表明,人参皂苷Rg1有望作为一种治疗选择,用于治疗对帕金森病敏感的人,尤其是经历高度压力和自我期望的人。
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Ginsenoside Rg1 ameliorates stress-exacerbated Parkinson's disease in mice by eliminating RTP801 and α-synuclein autophagic degradation obstacle.

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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来源期刊
Acta Pharmacologica Sinica
Acta Pharmacologica Sinica 医学-化学综合
CiteScore
15.10
自引率
2.40%
发文量
4365
审稿时长
2 months
期刊介绍: APS (Acta Pharmacologica Sinica) welcomes submissions from diverse areas of pharmacology and the life sciences. While we encourage contributions across a broad spectrum, topics of particular interest include, but are not limited to: anticancer pharmacology, cardiovascular and pulmonary pharmacology, clinical pharmacology, drug discovery, gastrointestinal and hepatic pharmacology, genitourinary, renal, and endocrine pharmacology, immunopharmacology and inflammation, molecular and cellular pharmacology, neuropharmacology, pharmaceutics, and pharmacokinetics. Join us in sharing your research and insights in pharmacology and the life sciences.
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