Lycium barbarum polysaccharides alleviate Parkinson's disease-induced neurodegeneration by up-regulating USP10 to modulate endoplasmic reticulum stress

Endoplasmic reticulum stress (ERS) is a significant pathological mechanism in Parkinson's disease (PD), and prolonged ERS can ultimately lead to cellular apoptosis. This study aimed to investigate the neuroprotective effects of Lycium barbarum polysaccharides (LBP) against MPP⁺-induced damage in Neural cells. The cells were treated with MPP⁺ for 24 hours, followed by LBP treatment for another 24 hours. Western blot analysis revealed that, compared to the Control group, MPP⁺ treatment upregulated the expression of GRP78, p-IRE1α, p-eIF2α, ATF-6, CHOP, caspase-3 and Bax, while downregulating Bcl-2. In contrast, LBP treatment significantly counteracted these effects by inhibiting the upregulation of ERS and pro-apoptotic markers and restoring Bcl-2 expression. Knockdown of ubiquitin-specific protease 10 (USP10) attenuated the protective effects of LBP in MPP⁺-injured Neural cells. Furthermore, co-immunoprecipitation and immunofluorescence co-localization assays confirmed an interaction between USP10 and Yes-associated protein 1 (YAP1). Deubiquitination experiments indicated that USP10 reduces YAP1 ubiquitination and enhances its protein stability. Additionally, we demonstrated that USP10 suppresses the PERK/eIF2α/ATF-4/CHOP pathway by inhibiting YAP1 ubiquitination, thereby alleviating MPP⁺-induced ERS and apoptosis. In summary, our findings indicate that LBP attenuates MPP⁺-induced neuronal injury by promoting USP10-mediated deubiquitination of YAP1 and subsequently inhibiting the PERK signaling pathway. These findings provide a novel direction and strategy for the clinical treatment of PD, as well as a new avenue for basic research in PD. Background : Endoplasmic reticulum stress (ERS) is an important pathogenesis of Parkinson's disease (PD). Chronic ERS can cause cell apoptosis. Lycium barbarum polysaccharides (LBP) are a type of protein polysaccharide with neuroprotective, anti-inflammatory, and anti-apoptotic effects, and have potential therapeutic effects on neurodegenerative diseases. Objective : This study aims to investigate the neuroprotective effect of LBP on MPP ⁺ -induced Neural cells and its potential molecular regulatory mechanism. Method : Neural cell was induced with MPP⁺ for 24 h, followed by LBP treatment for another 24 h. Neural cells were transfected with USP10 and YAP1 overexpression plasmids and specific siRNAs. The PERK pathway inhibitor GSK2606414 was employed to counteract the effects of YAP1 knockdown. Subsequent evaluations encompassed CCK-8 assay for cell viability, Western blotting for ERS related proteins, flow cytometry for cell apoptosis and mitochondrial membrane potential, immunofluorescence for protein localization, calcium probes for intracellular calcium homeostasis. The interaction between USP10 and YAP1 was verified by co-immunoprecipitation. Result : In neural cells, MPP ⁺ induces endoplasmic reticulum (ER) swelling, vacuolization, and intracellular calcium imbalance. It concurrently upregulates the expression of endoplasmic reticulum stress markers (GRP78, p-PERK, p-eIF2α, ATF-4, CHOP) and pro-apoptotic proteins (caspase-3, Bax), while downregulating the expression of the anti-apoptotic protein Bcl-2. These changes ultimately promote endoplasmic reticulum stress, oxidative stress, and cellular apoptosis. LBP alleviates these changes by restoring calcium homeostasis and downregulating stress and apoptosis-related proteins, an effect that is abolished by USP10 knockdown. USP10 mediates this protection by inhibiting YAP1 ubiquitination. Notably, the PERK inhibitor GSK2606414 reversed the enhanced expression of apoptotic and stress proteins resulting from YAP1 silencing. Conclusion : These results demonstrate that LBP exerts neuroprotective effects by alleviating MPP+-induced ERS and cell apoptosis. The underlying mechanism involves the upregulation of USP10-mediated deubiquitination of YAP1, which in turn suppresses the activity of the PERK signaling pathway. Our results provide a novel direction and strategy for the clinical treatment of PD, as well as a new avenue for basic research in PD.