Polymorphism in theVesicular Monoamine Transporter 2Gene Decreases the Risk of Parkinson’s Disease in Han Chinese Men

Abstract

Background. Polymorphisms rs363371 and rs363324 in the vesicular monoamine transporter 2 (VMAT2) gene have been associated with risk of PD in an Italian population, and our aim is to investigate the association between the two single-nucleotide polymorphisms and PD in Han Chinese. Methods. 561 Han Chinese PD patients and 491 healthy age- and gender-matched controls were genotyped using Ligase detection reaction (LDR) method. Result. Both of patient and control groups showed similar genotype frequencies between patients and controls at both rs363371 and rs363324, as well as similar minor A allele frequencies at rs363371 (P = 0.452) and rs363324 (P = 0.413). None of the observed haplotypes showed a significant association with PD. Subgroup analysis by gender and age at onset revealed a significant association between the A allele of rs363371 and PD in Han Chinese males relative to healthy controls (OR 0.799, 95% CI 0.665 to 0.959, P = 0.016), and this association remained significant after adjusting for age (OR 0.785, 95% CI 0.652 to 0.945, P = 0.011). Conclusion. These results suggest that polymorphism of VMAT2 locus is associated with risk of PD in Han Chinese overall but that the A allele at rs363371 may protect against PD in Han Chinese males.

Acquired dysregulation of dopamine homeostasis reproduces features of Parkinson’s disease

“…Furthermore, rare mutations in SLC18A2 result in infantile Parkinsonism [33][34][35] . In contrast, a number of studies have identified variants outside the coding region of SLC18A2 that increase expression of VMAT2 resulting in a gain-of-function and decreased likelihood of developing Parkinson's disease [36][37][38] . These studies suggest that increased sequestration of dopamine can be protective against the development of Parkinson's disease.…”

Tipping Points and Endogenous Determinants of Nigrostriatal Degeneration by MPTP

“…In a low-VMAT-2-expression mouse model, locus coeruleus noradrenergic neurons exhibited progressive degeneration even before the onset of nigrostriatal DA neurodegeneration [57]. Conversely, polymorphisms identified in the human VMAT-2 promoter region indicated that elevated VMAT-2 expression correlated with reduced PD risk [58,59]. Notably, mice exposed during development to dieldrin, an environmental toxicant, displayed an increased DAT:VMAT-2 ratio in the adult nigrostriatal system and, consequently, were more vulnerable to MPTP toxicity than were unexposed control mice [60].…”

Tricyclic and tetracyclic antidepressants upregulate VMAT2 activity and rescue disease-causing VMAT2 variants

“…A genetic study has found that alleles resulting in VMAT2 overexpression (rs363371 and rs363324) are associated with a lower risk of developing Parkinson’s disease in an Italian population [11]. A study with the Chinese Han population has replicated the result for the rs363371 allele in males, but not the other allele [12]. Another human study has reported gain-of-function VMAT2 haplotypes that result in overexpression of VMAT2 are associated with lower risk of developing Parkinson’s disease in females [13].…”

“…Our study aimed to identify compounds that could upregulate VMAT2 levels and activity since low VMAT2 levels are associated with BVMTD, Parkinson's disease, and depression, and high VMAT2 levels are protective for Parkinson's disease risk in Tricyclic and tetracyclic antidepressants upregulate VMAT2 activity… 4 humans and neurotoxicity in rodents [8][9][10][11][12][13][14][15][17][18]. We hypothesized that tricyclic antidepressants modulate VMAT2 activity since they are known to affect the monoamine transporters SERT and NET.…”