Differential expression of α-synuclein splice variants in the brain of alcohol misusers: Influence of genotype

Abstract

Background: Chronic alcohol misuse causes damage in the central nervous system that may lead to tolerance, craving and dependence. These behavioural changes are likely the result of cellular adaptations that include changes in gene expression. α-Synuclein is involved in the dopaminergic reward pathway, where it regulates dopamine synthesis and release. Previous studies have found that the gene for α-synuclein, SNCA, is differentially expressed in alcohol misusers. Methods: The present study measured the expression of three α-synuclein variants, SNCA-140, SNCA-112, and SNCA-115 in the prefrontal cortex of controls and alcohol misusers with and without cirrhosis of the liver. In addition, eight SNPs located in the 5'- and 3'-UTRs were genotyped in a Caucasian population of 125 controls and 115 alcohol misusers. Results: The expression of SNCA-140 and SNCA-112 was significantly lower in alcohol misusers with cirrhosis than in controls. However, SNCA-115 expression was significantly greater in alcohol misusers with cirrhosis than in controls. Allele and genotype frequencies differed significantly between alcohol misusers and controls for three SNPs, rs356221, rs356219 and rs2736995. Two SNPs, rs356221 and rs356219, were in high linkage disequilibrium. There was no increased risk of alcoholism associated with specific genotypes or haplotypes. Our results suggest that the rs356219/356221 G-A haplotype may decrease the chance of having an alcohol misuse phenotype. Conclusion: These findings suggest that alcohol misuse may alter the expression of the individual α-synuclein splice variants differently in human brain. There was no evidence of an effect of sequence variation on the expression of α-synuclein splice variants in this population.