文献类型：期刊文献

英文题名：Apigenin enhances Nrf2-induced chaperone-mediated autophagy and mitigates α-synuclein pathology: Implications for Parkinson's disease therapy

作者：Huang, Yi-Bin[1,2];Tian, Lu-Lu[3];Zhu, Zi-Wen[1];Zhou, Kai-Ge[1];Lai, Xue[2];Peng, Yan-Zi[1];Wu, Zhuang[4];Tong, Wei-Fang[1];Wang, Huan[5];Wang, Xi-Jin[1];Guan, Qiang[1];Jin, Ling-Jing[6];Feng, Ya[7];Weng, Wei-Yu[2];Zhang, Jing-Xing[1]

机构：[1]Tongji Univ, Tongji Hosp, Sch Med, Dept Neurol, Shanghai 200092, Peoples R China;[2]East China Univ Sci & Technol, Shanghai Key Lab New Drug Design, Shanghai 200237, Peoples R China;[3]Tongji Univ, Tongji Hosp, Sch Med, Dept Pharm, Shanghai 200065, Peoples R China;[4]Shanghai Jiao Tong Univ, Xinhua Hosp, Sch Med, Dept Neurol, Shanghai, Peoples R China;[5]Tongji Univ, Tongji Hosp, Clin Res Ctr, Sch Med, Shanghai, Peoples R China;[6]Tongji Univ, Shanghai Yangzhi Rehabil Hosp, Sch Med, Dept Neurol & Neurol Rehabil, Shanghai 200092, Peoples R China;[7]Shanghai Jiao Tong Univ, Sch Med, Shanghai Gen Hosp, Dept Neurol, Shanghai 200080, Peoples R China

年份：2025

卷号：141

外文期刊名：PHYTOMEDICINE

收录：;WOS:【SCI-EXPANDED(收录号:WOS:001469803400001)】；

语种：英文

外文关键词：Parkinson's disease; Apigenin; Chaperone-mediated autophagy; alpha-synuclein; Nuclear factor erythroid 2-related factor 2; (Nrf2); Extracellular regulated protein kinases (ERK)

摘要：Background: The aggregation of alpha-synuclein (SNCA) in dopaminergic neurons of the substantia nigra is a key factor in the pathogenesis of Parkinson's disease (PD). Despite years of drug discovery efforts targeting SNCA aggregation, no disease-modifying drugs have been approved to date. The failure of numerous clinical trials can be attributed, at least in part, to the difficulty in identifying potent compounds during preclinical investigations. Objective: Establish a screening approach based on molecular docking and autophagic flux detection to identify natural compounds from new perspectives of SNCA clearance and to explore its mechanism. Methods: Molecular docking technique combined with autophagic flux detection was performed for preliminary screening of flavonoids in PubChem and CHEBI databases. Western blotting was utilized to detect the levels of SNCA, chaperone-mediated autophagy (CMA)-associated proteins, apoptosis-related proteins, and neuroinflammatory biomarkers, alongside the assessment of phosphorylation status of proteins implicated in signaling cascades. JC-1 staining was used to measure the mitochondrial transmembrane potential (MMP). RNAsequencing and Kyoto encyclopedia of genes and genomes/gene ontology (KEGG/GO) analysis were optimized to detect gene expression. PD mouse motor function was assessed using rotarod, pole, open field, footprint, and gait analyses. Immunofluorescence staining was employed to detect the expression of Nuclear factor erythroid 2-related factor 2 (Nrf2), dopaminergic neuronal deficits, microglia activation, and production of inflammatory factors. LysoTracker Red staining and pSIN-PAmCherry-KFERQ-NE plasmid were used to evaluate the lysosomal activity. pHrodoTM Green E.coli BioParticlesTM were employed to measure phagocytosis activity. identified apigenin (AP) as a candidate that activates CMA to promote SNCA clearance and thereby inhibits SNCA-induced neurotoxicity. AP inhibited apoptosis by promoting SNCA degradation through Nrf2-mediated CMA activation. Moreover, AP could also inhibit apoptosis via the Nrf2/extracellular regulated protein kinases (ERK) feedback loop that operates independently of CMA activation. Additionally, AP enhanced the phagocytosis capabilities of BV2 cells and inhibited SNCA-induced neuroinflammation, both in vitro and in vivo. Conclusions: AP activates CMA to promote the clearance of SNCA, thereby inhibiting SNCA-induced neurotoxicity. Nrf2 and its role in AP-mediated neuroprotection may provide new insights that target degradation pathways to counteract SNCA pathology in PD.