CircEPS15, as a sponge of MIR24-3p ameliorates neuronal damage in Parkinson disease through boosting PINK1-PRKN-mediated mitophagy

ABSTRACTDespite growing evidence that has declared the importance of circRNAs in neurodegenerative diseases, the clinical significance of circRNAs in dopaminergic (DA) neuronal degeneration in the pathogenesis of Parkinson disease (PD) remains unclear. Here, we performed rRNA-depleted RNA sequencing and detected more than 10,000 circRNAs in the plasma samples of PD patients. In consideration of ROC and the correlation between Hohen-Yahr stage (H-Y stage) and Unified Parkinson Disease Rating Scale-motor score (UPDRS) of 40 PD patients, circEPS15 was selected for further research. Low expression of circEPS15 was found in PD patients and there was a negative positive correlation between the circEPS15 level and severity of PD motor symptoms, while overexpression of circEPS15 protected DA neurons against neurotoxin-induced PD-like neurodegeneration in vitro and in vivo. Mechanistically, circEPS15 acted as a MIR24-3p sponge to promote the stable expression of target gene PINK1, thus enhancing PINK1-PRKN-dependent mitophagy to eliminate damaged mitochondria and maintain mitochondrial homeostasis. Thus, circEPS15 rescued DA neuronal degeneration through the MIR24-3p-PINK1 axis-mediated improvement of mitochondrial function. This study reveals that circEPS15 exerts a critical role in participating in PD pathogenesis, and may give us an insight into the novel avenue to develop potential biomarkers and therapeutic targets for PD.Abbreviations: AAV: adeno-associated virus; DA: dopaminergic; FISH: fluorescence in situ hybridizations; HPLC: high-performance liquid chromatography; H-Y stage: Hohen-Yahr stage; LDH: lactate dehydrogenase; MMP: mitochondrial membrane potential; MPTP/p: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/probenecid; NC: negative control; PD: Parkinson disease; PINK1: PTEN induced kinase 1; PBS: phosphate-buffered saline; ROS: reactive oxygen species; SNpc: substantia nigra pars compacta; TEM: transmission electron microscopy; UPDRS: Unified Parkinson’s Disease Rating Scale-motor scoreKEYWORDS: CircEPS15MIR24-3pmitophagyParkinson diseasePINK1 AcknowledgementsWe would like to thank Dr. Lei Cao from the Department of Pharmacology, National University of Singapore, for his helpful suggestions on the manuscript.Disclosure statementNo potential conflict of interest was reported by the author(s).Data availability statementAll data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. Additional data related to this paper may be requested from the authors.Ethics approval and consent to participateAll experiments involving serum samples of PD patients were approved by the Committee of Nanjing Medical University (NJMU-2019-784). All animal experiments were approved by the Institutional Animal Care and Use Committee of Nanjing Medical University (1601153–3) and complied with institutional guidelines.Supplementary materialSupplemental data for this article can be accessed online at https://doi.org/10.1080/15548627.2023.2196889.Additional informationFundingThe work reported herein was supported by grants from the National Key R&D Program of China [No.2021ZD0202903], the National Natural Science Foundation of China [No.81922066, No.82173797, No.82003725, No.81991523 and No.82003722].