Risk and protective haplotypes of the alpha-synuclein gene associated with Parkinson's disease differentially affect cognitive sequence learning

Alpha-synuclein (SNCA) is a key factor in the regulation of dopaminergic transmission and is related to Parkinson's disease. In this study, we investigated the effects of risk and protective SNCA haplotypes associated with Parkinson's disease on cognitive sequence learning in 204 healthy volunteers. We found that the 3′-block risk SNCA haplotypes are associated with less effective stimulus-reward learning of sequences and with superior context representation of sequences. In contrast, participants with protective haplotypes exhibit better stimulus-reward learning and worse context representation, which suggest that these functions are inversely affected by risk and protective haplotypes. The Rep1 promoter polymorphism does not influence cognitive sequence learning. Because stimulus-reward learning may be mediated by the basal ganglia and context learning may be related to the medial temporal lobe, our data raise the possibility that dopaminergic signals regulated by SNCA inversely affect these memory systems.