CircSV2b participates in oxidative stress regulation through miR-5107-5p-Foxk1-Akt1 axis in Parkinson's disease

As a novel type of non-coding RNAs, covalently closed circular RNAs (circRNAs) are ubiquitously expressed in eukaryotes. Emerging studies have indicated that dysregulation of circRNAs was related to neurological diseases. However, the biogenesis, regulation, function, and mechanism of circRNAs in Parkinson's disease (PD) remain largely unclear. In this study, thirty-three differentially expressed circRNAs (DECs) were detected by RNA-sequencing between the MPTP-induced PD mice model and the wild-type mice. Quantitative real-time PCR was used to determine the RNA level of DECs in the striatum (STR), substantia nigra pars  compacta (SNpc), and serum exosomes, and it was found that circSV2b was downregulated in PD mice. Then, functional experiments in vivo were employed to explore the effect of circSV2b in PD. For the mechanism study, dual-luciferase reporter, fluorescence in situ hybridization (FISH), RNA immunoprecipitation (RIP),RNA pull-down, gene editing, and CUT & Tag were performed in vitro to confirm that circSV2b directly sponged miR-5107-5p and alleviated the suppression of the expression of the target gene Foxk1, and then positively regulated Akt1 transcription.In vivo, the mechanistic analysis demonstrated that circSV2b overexpression resisted oxidative stress damage through the ceRNA-Akt1 axis in PD models. Taken together,these findings suggested that the miR-5107-5p-Foxk1-Akt1 axis might serve as a key target of circSV2b overexpression in PD treatment, and highlighted the significant change of circSV2b in serum exosomes. Therefore, circSV2b might be a novel biomarker for the diagnosis and treatment of PD.

Keywords: circSV2b, miR-5107-5p, Foxk1, Akt1, oxidative stress