Analysis of vesicular monoamine transporter 2 polymorphisms in Parkinson’s disease

Abstract

Generation of reactive oxygen species during dopamine (DA) oxidation could be one of the factors leading to the selective loss of nigral dopaminergic neurons in Parkinson’s disease (PD). Vesicular monoamine transporter type 2 (VMAT2) proteins in nerve terminals uptake dopamine into synaptic vesicles, preventing its cytoplasmic accumulation and toxic damage to nigral neurons. Polymorphisms in VMAT2 gene and in its regulatory regions might therefore serve as genetic risk factors for PD. In the present study, we have analyzed 8 single-nucleotide polymorphisms (SNPs) located within/around the VMAT2 gene for association with PD in an Italian cohort composed of 704 PD patients and 678 healthy controls. Among the 8 SNPs studied, only the 2 located within the promoter region (rs363371 and rs363324) were significantly associated with PD. In the dominant model, odds ratios were 0.72 (95% confidence interval [CI]: 0.6–0.9, p < 0.005) for rs363371 and 0.76 (95% CI: 0.6–0.9, p = 0.01) for rs363324; in the additive model, odds ratios were 0.78 (95% CI: 0.65–0.94, p = 0.008) for rs363371 and 0.85 (95% CI: 0.7–20.92, p = 0.04) for rs363324. There were no significant relationships between the remaining SNPs (rs363333, rs363399, rs363387, rs363343, rs4752045, and rs363236) and the risk of sporadic PD in any genetic model. This study adds to the previous evidence suggesting that variability in VMAT2 promoter region may confer a reduced risk of developing PD, presumably via mechanisms of gene overexpression.

Fungal-derived semiochemical 1-octen-3-ol disrupts dopamine packaging and causes neurodegeneration

“…Previous studies modeling Parkinson disease in Drosophila demonstrated that overexpression of the vesicular monoamine transporter promotes packaging of dopamine into vesicles, thereby lowering its cytoplasmic concentrations (19,39). Human genetic studies have found that single nucleotide polymorphisms (SNPs) within the promoter region of VMAT2, in particular gain-of-function haplotypes, are also associated with decreased risk of PD in women (40). Furthermore, in mice, reduced VMAT2 function produces dopamine-mediated toxicity and neurodegeneration in the nigrostriatal dopamine system, and restoration of VMAT2 function may be an important intervention in the treatment of PD (41)(42)(43)(44).…”

Increased vesicular monoamine transporter enhances dopamine release and opposes Parkinson disease-related neurodegeneration in vivo

“…disease (29,30). Although the detrimental effects of reduced VMAT2 function are recognized, our understanding of the potential benefits of increased VMAT2 function in vivo has been limited to a Drosophila model (31)(32)(33).…”

Identification of potential drugs for Parkinson's disease based on a sub-pathway method

“…The top five up and down-regulated DEGs were shown in the Table 1. Among these genes, solute carrier family 18 (SLC18A2), expressed in central, peripheral, and enteric neurons as well as in platelets [20], is capable of uptaking dopamine into intracellular secretory vesicles, preventing its toxicity in the cytosol and discharging it into the extracellular space by exocytosis [21]. Study has showed that SLC18A2 messenger RNA (mRNA) levels were reduced in platelets from PD patients [22].…”