miR-486-3p Influences the Neurotoxicity of a-Synuclein by Targeting the SIRT2 Gene and the Polymorphisms at Target Sites Contributing to Parkinson's Disease.

ABSTRACT

BACKGROUND/AIMS: Increasing evidence suggests the important role of sirtuin 2 (SIRT2) in the pathology of Parkinson's disease (PD). However, the association between potential functional polymorphisms in the SIRT2 gene and PD still needs to be identified. Exploring the molecular mechanism underlying this potential association could also provide novel insights into the pathogenesis of this disorder. METHODS: Bioinformatics analysis and screening were first performed to find potential microRNAs (miRNAs) that could target the SIRT2 gene, and molecular biology experiments were carried out to further identify the regulation between miRNA and SIRT2 and characterize the pivotal role of miRNA in PD models. Moreover, a clinical case-control study was performed with 304 PD patients and 312 healthy controls from the Chinese Han population to identify the possible association of single nucleotide polymorphisms (SNPs) within the miRNA binding sites of SIRT2 with the risk of PD. RESULTS: Here, we demonstrate that miR-486-3p binds to the 3' UTR of SIRT2 and influences the translation of SIRT2. MiR-486-3p mimics can decrease the level of SIRT2 and reduce a-synuclein (α-syn)-induced aggregation and toxicity, which may contribute to the progression of PD. Interestingly, we find that a SNP, rs2241703, may disrupt miR-486-3p binding sites in the 3' UTR of SIRT2, subsequently influencing the translation of SIRT2. Through the clinical case-control study, we further verify that rs2241703 is associated with PD risk in the Chinese Han population. CONCLUSION: The present study confirms that the rs2241703 polymorphism in the SIRT2 gene is associated with PD in the Chinese Han population, provides the potential mechanism of the susceptibility locus in determining PD risk and reveals a potential target of miRNA for the treatment and prevention of PD.