Rs2015 Polymorphism in miRNA Target Site of Sirtuin2 Gene Is Associated with the Risk of Parkinson’s Disease in Chinese Han Population

Abstract

Accumulating evidence reveals that the sirtuin family is involved in the pathology of Parkinson’s disease (PD). However, the association between the polymorphisms of the sirtuin gene and the risk of PD remains elusive. Here, we investigated the possible association of nine SIRT1 and SIRT2 SNPs with the risk of PD through a clinical case-control study from the Chinese Han population. Our results showed that rs12778366 in the promoter region of SIRT1 and rs2015 in the 3′untranslated region (3′UTR) of the SIRT2 were significantly associated with the risk of PD. Five SNPs related to SIRT1, rs3740051, rs7895833, rs7069102, rs2273773, and rs4746720 and two SNPs related to SIRT2, rs10410544, and rs45592833 did not show an association with PD risk in this study. Moreover, we found that mRNA level of SIRT2 was upregulated, and mRNA level of SIRT1 was downregulated in the peripheral blood of PD patients compared with healthy controls, and we also observed that SNPs rs12778366 and rs2015 influenced the SIRT1 and SIRT2 expression levels, respectively. Further functional assays suggest that rs2015 may affect the expression of SIRT2 by affecting the binding of miR-8061 to the 3′UTR of SIRT2, ultimately contributing to the risk of PD.

Understanding the Potential Role of Sirtuin 2 on Aging: Consequences of SIRT2.3 Overexpression in Senescence

“…Second, an increase in SIRT2 levels has been described in different neuropsychiatric and neurodegenerative diseases including AD [ 29 , 39 ], PD [ 50 , 59 , 60 , 61 ], and Huntington’s disease (HD) [ 62 ], both in mouse models and human postmortem brain tissues ( Table 2 ). Moreover, SIRT2 deletion or pharmacological inhibition has provided beneficial effects in different neurodegenerative diseases.…”

Gene variants and expression changes of SIRT1 and SIRT6 in peripheral blood are associated with Parkinson’s disease

“…Moreover, this study reported down-regulated SIRT1 expression, and up-regulated SIRT2 mRNA level in PD patients as compared to non-PD controls. These gene expression changes correlated with the presence of the rs12778366 of SIRT1 and r2015 of SIRT2 variants 21 . Results of a meta-analysis by Nicholatos et al .…”

“…In recent years a growing body of evidence has accumulated on the importance of SIRTs in PD pathogenesis 6 . SIRT1 and SIRT2 seem to have opposite effects on the development and course of the disease 21 . A recent meta-analysis revealed strong association between SIRT6 polymorphisms and PD, suggesting a pathogenic role of SIRT6 in the disease 17 .…”

“…Recently, Chang et al reported an association between the occurrence of PD and the rs12778366 SNP in Han Chinese population. Chang and colleagues proposed that rs12778366, which is localized in the promoter region of SIRT1, might influence the expression of the gene 21 . Our results show no significant association between the rs12778366 SNP and PD, and we detected no effect of the minor allele on gene expression.…”

Sirtuin 2 (SIRT2): Confusing Roles in the Pathophysiology of Neurological Disorders

“…Previous studies have corroborated that specific SIRT2 single-nucleotide polymorphisms (SNPs) correlate to the risk of a number of neurodegenerative diseases, like Alzheimer's disease (AD) (Polito et al, 2013;Porcelli et al, 2013;Xia et al, 2014;Cacabelos et al, 2019;Shen et al, 2020) and Parkinson's disease (PD) (Wang et al, 2018;Chen et al, 2019) under certain conditions. Recent studies demonstrated that SIRT2 participates in even more pathological processes such as frontotemporal dementia (FTD) (Spires-Jones et al, 2012), stroke (Shu et al, 2019), and brain injury (Wang et al, 2016).…”