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.

Haplotypes of the Mutated SIRT2 Promoter Contributing to Transcription Factor Binding and Type 2 Diabetes Susceptibility

“…In addition, several genetic polymorphisms of the SIRT2 gene have been identified in Chinese populations. For instance, an SNP locus (rs2241703) in the 3'UTR of the SIRT2 gene, which disrupted the binding site of miR-486-3p, was associated with the risk of Parkinson's disease [33]. Another polymorphism rs2241703 of SIRT2 was reported to affect Alzheimer's disease [34].…”

Regulation of Hypoxic Signaling and Oxidative Stress via the MicroRNA–SIRT2 Axis and Its Relationship with Aging-Related Diseases

“…In addition to the miR-212-5p–SIRT2 axis, the regulation of SIRT2 by other miRNAs in Parkinson’s disease has been reported. miR-486-3p binds to the 3′-UTR of SIRT2, and single nucleotide polymorphisms (SNPs), such as rs2241703, in this binding site were identified in Parkinson’s disease patients [ 87 ]. Another study also identified an SNP, rs2015, in the target site of miR-8061 in the 3′-UTR of SIRT2, which was shown to contribute to the risk of Parkinson’s disease [ 88 ].…”

Intestinal flora imbalance affects the prognosis of Parkinson's disease by regulating the expression of fecal microRNA-146a and GDNF: A Preliminary Study

“…Moreover, the expression of miR-181 was also demonstrated to influence gut dysbiosis and contribute to the development of obesity and insulin resistance [14]. In this study, we selected several candidate miRNAs, including miR-486-3p [15], miR-96 [16], miR-342-3p [17], miR-155 [18], miR-146a [19,20], miR-34a [21], miR-182 [22], miR-183 [22], miR-505 [23] and miR-221 [24], and studied their possible role in intestinal flora imbalance during the progression of PD.…”