Polymorphisms of the alpha-synuclein promoter: expression analyses and association studies in Parkinson's disease.

Mutations of the α-synuclein gene have shown to be relevant in some rare families with autosomal dominant Parkinson's disease (PD). Furthermore, α-synuclein protein is a major component of the Lewy bodies also in sporadic PD patients. Increased levels of wildtype α-synuclein in the cell leads to increased intracellular hydrogen peroxide levels and causes death of dopaminergic neurons in rat primary culture. Subsequently, oxidative stress has been directly linked with α-synuclein aggregation in vitro. This raises the question whether increased α-synuclein expression might be linked to higher susceptibility to PD and whether α-synuclein promoter polymorphisms are associated with PD. Here, two polymorphisms (−116C>G and −668T>C) of the α-synuclein promoter defining four haplotypes have been characterized in 315 German PD patients. The influence of the four haplotypes on gene expression was studied by CAT reporter gene assays in neuronal SK-N-AS cells. The −668C/−116G haplotype revealed significant higher CAT expression than the −668T/−116G or the −668T/−116C haplotype, respectively. Although the −668C/−116G haplotype was more common in PD patients, this difference was not significant.