CircSNCA downregulation by pramipexole treatment mediates cell apoptosis and autophagy in Parkinson’s disease by targeting miR-7

Abstract

We aimed to explore the mechanism of pramipexole (PPX) actions in the treatment of Parkinson’s disease (PD). Genes related to PD and PPX were screened through bioinformatics retrieval. The PD model was constructed by applying 1-methyl-4-phenylpyridinium (MMP+). The RNA expression levels of circSNCA, SNCA, apoptosis-related genes (BCL2, CASP3, BAX, PTEN and P53) and miR-7 were detected by qRT-PCR. Protein expression was determined by western blot. The interactions between circSNCA-miR-7-SNCA were verified by dual luciferase assay and immunofluorescence localization. Cell viability was determined by MTT assay. SNCA and circSNCA expression levels in PD were downregulated after PPX treatment, consistent with the levels of pro-apoptotic genes. CircSNCA increased SNCA expression by downregulating miR-7 in PD as a competitive endogenous RNA (ceRNA). Lower circSNCA expression was associated with the reduced expression of pro-apoptotic (CASP3, BAX, PTEN and P53) proteins. CircSNCA downregulation could decrease apoptosis and induce autophagy in PD. In conclusion, the downregulation of circSNCA by PPX treatment reduced cell apoptosis and promoted cell autophagy in PD via a mechanism that served as a miR-7 sponge to upregulate SNCA.

Current status and potential role of circular RNAs in neurological disorders

“…These results also suggested a possible sponge effect between ciRS‐7 and miR‐7 in vitro . In addition, another circRNA called circSNCA can sponge miR‐7, thereby up‐regulating expression of SNCA mRNA, resulting in reduced autophagy and increased apoptosis in SH‐SY5Y cells (Sang et al ). The findings were consistent with the results of a study by Ghavami et al, which showed that autophagy can prevent PD (Ghavami et al ), and that of Kountouras et al, which showed that apoptosis is associated with PD (Kountouras et al ).…”

“…Agents such as inorganic metals, pesticides, and psychostimulants can induce neurotoxicity (Liu et al ; Xiong et al ; Zhang et al ; Sang et al ; Yang et al ; Gao et al ). Because of the significant impacts on human health caused by neurotoxic agents, there is considerable demand to characterize the biological signals and markers associated with exposure to these agents (Roberts et al ; Yang et al ).…”

Circular RNAs and Its Biological Functions in Health and Disease

“…Furthermore, the silencing of ciRS-7 increases miR-7 activity and decreases the expression of miR-7 target genes [110]. In addition, circSNCA, another circRNA, can sponge miR-7, thereby regulating expression of SNCA, resulting in decreased autophagy and increased apoptosis in cells [111]. These findings are in concordance with the results of a study, which showed that autophagy can prevent PD [112], and that of the other study, which demonstrated that apoptosis is related to PD [113].…”

Functional roles and networks of non-coding RNAs in the pathogenesis of neurodegenerative diseases

“…Thus, clearance of neurotoxic aggregates is a major focus of phenotypic assays for drug development, including those that measure autophagy-lysosomal network function and ubiquitinproteasome-mediated protein degradation. Other assays measure endpoints related to cellular viability or neuronal death, such as caspase-dependent apoptosis [12], oxidative stress-induced mitochondrial dysfunction [13], and neurotrophic factor expression [14]. Current platforms for modeling neurodegeneration include a combination of patient-derived induced pluripotent stem cells (iPSCs), cellular models and animal models, which all recapitulate at least some disease-relevant phenotypes [6].…”