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.
Tagliafierro, L; Glenn, O-C; Zamora, ME; Beach, TG; Woltjer, RL; Lutz, MW; Chiba-Falek, O
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