Lack of Association Between DJ-1 Gene Promoter Polymorphism and the Risk of Parkinson's Disease.

Lu He,Yuyan Tan,Mengyan Wang,Ruinan Shen,Shengdi Chen,Ying Wang,Shiyao Sun,Suzhen Lin,Zhihao Liu,Jianqing Ding,Hong Pan

doi:10.3389/fnagi.2019.00024

Abstract

Low DJ-1 protein level caused by DJ-1 gene mutation leads to autosomal recessive Parkinson’s disease (PD) due to impaired antioxidative activity. In sporadic PD patients, although mutations were rarely found, lower DJ-1 protein level was also reported. Dysregulation of DJ-1 gene expression might contribute to low DJ-1 protein level. Since the promoter is the most important element to initiate gene expression, whether polymorphisms in the DJ-1 promoter result in the dysregulation of gene expression, thus leading to low protein level and causing PD, is worth exploring. The DJ-1 promoter region was sequenced in a Chinese cohort to evaluate possible links between DJ-1 promoter polymorphisms, PD risk and clinical phenotypes. Dual-luciferase reporter assay was conducted to evaluate the influence of promoter polymorphisms on DJ-1 transcriptional activity. Related information in an existing genome-wide association studies (GWAS) database were looked up, meta-analysis of the present study and other previous reports was conducted, and expression quantitative trait loci (eQTL) analysis was performed to further explore the association. Three single nucleotide polymorphisms (SNPs) (rs17523802, rs226249, and rs35675666) and one 18 bp deletion (rs200968609) were observed in our cohort. However, there was no significant association between the four detected genetic variations and the risk of PD either in allelic or genotype model, in single-point analysis or haplotype analysis. This was supported by the meta-analysis of this study and previous reports as well as that of GWAS database PDGene. Dual luciferase reporter assay suggested these promoter polymorphisms had no influence on DJ-1 transcriptive activity, which is consistent with the eQTL analysis results using the data from GTEx database. Thus, DJ-1 promoter polymorphisms may play little role in the dysregulation of DJ-1 expression and PD susceptibility in sporadic PD.

Highlights

Parkinson’s disease (PD) is a common neurodegenerative disorder affecting approximately 1% of people over the age of 60 of the world and 1.7% of people over 65 in China (Zhang et al, 2005; de Lau and Breteler, 2006)
Disease duration, Hoehn and Yahr stage and oral Levodopa Equivalent Dose (LED)/day showed different distribution among three PD motor subtypes: There were more male patients in the AR group; Tremor Dominant (TD) group consisted of more early stage PD patients compared to AR and MX group
In familial PD, such deficiency is caused by mutations in DJ-1 gene, whereas in sporadic PD, who lacks mutations in DJ-1, the reason of a low brain DJ-1 protein level remains obscure

Summary

Introduction

Parkinson’s disease (PD) is a common neurodegenerative disorder affecting approximately 1% of people over the age of 60 of the world and 1.7% of people over 65 in China (Zhang et al, 2005; de Lau and Breteler, 2006). Loss of function mutations in the DJ-1 gene, including deletion of exon 1-5 (Bonifati et al, 2003), L166P (Bonifati et al, 2003), R98Q (AbouSleiman et al, 2003; Hague et al, 2003), M26I (Abou-Sleiman et al, 2003), E64D (Hering et al, 2004), and L172Q (Taipa et al, 2016), have been demonstrated to cause degeneration of dopamine neurons and autosomal recessive inherited PD These causative mutations explained less than 10% of PD patients since about 90% of cases are sporadic without these mutations (Sutherland et al, 2009). The mechanism of low DJ-1 protein level in sporadic PD is still obscure

Methods

Results

Conclusion