Hsa_Circ_0105596/FTO inhibits progression of Parkinson's disease by sponging miR-187-3p and regulating eEF2.

BACKGROUND

Parkinson's disease (PD) characterized by inflammation and protein erroneous deposition, whose pathological mechanisms have not been elucidated. NcRNA plays important role in PD, especially when circRNA sponges miRNA, which leads to the breakdown of downstream regulation. The aim of this study is to investigate the dynamic changes between upregulated circRNA and downregulated miRNA during the pathogenesis of PD and their impact on downstream miRNA targets.

METHOD

We conducted bioinformatics on sequencing data of substantia nigra (SN) and striatum, and intersected differentially expressed genes (Degs) to determine core role of circFTO-miR-187-3p-EEF2 axes in the progression of PD. Firstly, therapeutic effect of knock-down circFTO in PD and its impact on EEF2 were determined in mouse, using immunohistochemistry, HE, Nissl, TUNEL staining and Western blot (WB). Targeted binding relationship between circFTO, miR-187-3p, and EEF2 was determined through RNA binding protein immunoprecipitation assays (RIP) and dual luciferase reporter assay. The significance of gene in apoptosis was confirmed through flow cytometry, lentiviral transduction, quantitative real-time PCR, and WB.

RESULT

CircFTO is upregulated and miR-187-3p is downregulated in SN of PD. EEF2 was the core of neural repair related modules in both SN and striatum using Weighted Correlation Network Analysis (WGCNA) and protein-protein interaction (PPI). The binding regulation relationship between circFTO-miR-187-3p-EEF2 was determined through structural analysis, RIP, and dual luciferase reporter assay. After knocking-down circFTO, animals showed alleviated symptoms, decreased levels of oxidative stress and EEF2. Upregulation of miR-187-3p or si-circFTO in SH-SY5Y cells can reduce cell apoptosis, EEF2, and oxidative stress. Moreover, individual interference with EEF2 can partially counteract the induction of 6-OHDA on apoptosis.

CONCLUSION

Excessive circFTO sponging miR-187-3p leads to the inability of miR-187-3p to effectively regulate expression of EEF2, resulting in the progression of PD. Moreover, interference with circFTO can effectively reduce brain inflammation and oxidative stress.