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Updated: Sep 15, 2025
Gene-environment Interaction Models to Unmask Susceptibility Mechanisms in Parkinson's Disease
Published on: January 7, 2014
Celastrol protected the MPTP-injected mice Parkinson's disease model via redox regulation of CDC37
Wanfen Liao1, Aiwen Dong1, Fatima Hafeez1
1Key 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.
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.
