Genetic analysis of α-synuclein 3′ untranslated region and its corresponding microRNAs in relation to Parkinson's disease compared to dementia with Lewy bodies

Introduction The α-synuclein (SNCA) gene has been implicated in the etiology of Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Methods A computational analysis of SNCA 3′ untranslated region to identify potential microRNA (miRNA) binding sites and quantitative real-time polymerase chain reaction (PCR) to determine their expression in isogenic induced pluripotent stem cell–derived dopaminergic and cholinergic neurons as a model of PD and DLB, respectively, were performed. In addition, we performed a deep sequencing analysis of the SNCA 3′ untranslated region of autopsy-confirmed cases of PD, DLB, and normal controls, followed by genetic association analysis of the identified variants. Results We identified four miRNA binding sites and observed a neuronal-type–specific expression profile for each miRNA in the different isogenic induced pluripotent stem cell–derived dopaminergic and cholinergic neurons. Furthermore, we found that the short structural variant rs777296100-polyT was moderately associated with DLB but not with PD. Discussion We suggest that the regulation of SNCA expression through miRNAs is neuronal-type–specific and possibly plays a part in the phenotypic heterogeneity of synucleinopathies. Furthermore, genetic variability in the SNCA gene may contribute to synucleinopathies in a pathology-specific manner.