雷公藤红素通过对细胞周期蛋白依赖性激酶37（CDC37）的氧化还原调节作用，对注射1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）的小鼠帕金森病模型起到保护作用。
Celastrol protected the MPTP-injected mice Parkinson's disease model via redox regulation of CDC37.
作者信息
Liao Wanfen, Dong Aiwen, Hafeez Fatima, Ye Qinyong, Huang En
机构信息
Key Laboratory of Brain Aging and Neurodegenerative Diseases of Fujian Province, Scientific Research Center, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian Province, China.
Department of Neurology, Fujian Medical University Union Hospital, Fujian Key Laboratory of Molecular Neurology and Institute of Neuroscience, Fujian Medical University, Fuzhou, China.
出版信息
Phytomedicine. 2025 Sep;145:157067. doi: 10.1016/j.phymed.2025.157067. Epub 2025 Jul 9.
BACKGROUND
Celastrol (CEL), a bioactive compound isolated from Tripterygium Wilfordii Hook. F, exerts neuroprotective effects through anti-oxidative, anti-inflammatory, and anti-apoptotic mechanisms in several neurodegenerative diseases, including Parkinson's disease (PD). CEL covalently binds to the thiol group of cysteine residues in cell division cycle 37 (CDC37), leading to redox-dependent modulation of CDC37 function. However, whether CEL redox regulates CDC37 and CEL-CDC37 interaction plays a role in pathogenesis of PD is still not be investigated yet. This study aids to demonstrate the role of CEL redox regulation of CDC37 in an MPTP-induced mouse model of PD.
METHODS
Lentiviral vectors were used to overexpress or knock down CDC37 in MPTP-injected mice. CEL was administered to assess its effect on CDC37 redox status and related molecular pathways.
RESULTS
CDC37 overexpression alleviated MPTP-induced motor deficits and dopaminergic neuron loss, whereas CDC37 knockdown exacerbated these impairments. Overexpression of CDC37 also suppressed activation of the NF-κB pathway and reduced phosphorylation of α-synuclein at serine 129 (p-S129-syn). MPTP insult decreased the reduced (active) form of CDC37 due to oxidative stress. CEL treatment restored CDC37 redox status, improved locomotor performance, preserved dopaminergic neurons, and inhibited both NF-κB activation and p-S129-synuclein levels. These effects were mediated by CEL's redox regulation of CDC37, which prevented its overoxidation, disrupted the Hsp90/CDC37 complex, and suppressed downstream pro-inflammatory and pro-pathogenic signaling.
CONCLUSION
Our study suggests that CEL restores the protective role of CDC37 in the MPTP-injected Parkinson's disease (PD) mouse model via redox regulation of CDC37, which prevents over-oxidation of CDC37 under high oxidative stress, and disrupts the Hsp90/CDC37 complex and subsequently blocks NF-κB pathway activation and p-S129-synuclein production. This study might provide a promising strategy for PD and further understanding of the therapeutic mechanism of CEL application.
背景
雷公藤红素（CEL）是从雷公藤中分离出的一种生物活性化合物，在包括帕金森病（PD）在内的几种神经退行性疾病中，通过抗氧化、抗炎和抗凋亡机制发挥神经保护作用。CEL与细胞分裂周期37（CDC37）中半胱氨酸残基的巯基共价结合，导致CDC37功能的氧化还原依赖性调节。然而，CEL氧化还原是否调节CDC37以及CEL-CDC37相互作用在PD发病机制中是否起作用仍未得到研究。本研究有助于证明CEL氧化还原调节CDC37在MPTP诱导的PD小鼠模型中的作用。
方法
使用慢病毒载体在注射MPTP的小鼠中过表达或敲低CDC37。给予CEL以评估其对CDC37氧化还原状态和相关分子途径的影响。
结果
CDC37过表达减轻了MPTP诱导的运动缺陷和多巴胺能神经元损失，而CDC37敲低加剧了这些损伤。CDC37过表达还抑制了NF-κB途径的激活，并降低了丝氨酸129（p-S129-syn）处α-突触核蛋白的磷酸化。MPTP损伤由于氧化应激降低了CDC37的还原（活性）形式。CEL处理恢复了CDC37的氧化还原状态，改善了运动性能，保护了多巴胺能神经元，并抑制了NF-κB激活和p-S129-突触核蛋白水平。这些作用是由CEL对CDC37的氧化还原调节介导的，它防止了CDC37的过度氧化，破坏了Hsp90/CDC37复合物，并抑制了下游促炎和致病信号。
结论
我们的研究表明，CEL通过对CDC37的氧化还原调节恢复了CDC37在MPTP注射的帕金森病（PD）小鼠模型中的保护作用，这防止了高氧化应激下CDC37的过度氧化，破坏了Hsp90/CDC37复合物，随后阻断了NF-κB途径激活和p-S129-突触核蛋白的产生。本研究可能为PD提供一种有前景的策略，并进一步了解CEL应用的治疗机制。
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