THE DISTINCT CONTRIBUTION OF SNCA-3′UTR TO PARKINSON’S AND DEMENTIA WITH LEWY BODIES

Abstract

The alpha-synuclein (SNCA) gene has been implicated in the etiology of Parkinson's disease (PD) and Dementia with Lewy Bodies (DLB). Both diseases share a common pathological hallmark, Lewy bodies (LBs) and Lewy-related neurites however, each disease presents distinct characteristics. Furthermore, GWAS results reported that variants defining the genetic association of the SNCA gene with PD are distinct from those SNCA-variants associated with DLB. However, the common and diverse molecular mechanisms by which SNCA genetic variants exert their effects on PD and DLB are not fully understood. A computational analysis of the SNCA-3’UTR was completed to identify potential microRNA binding-sites. Next, we used two complementary approaches. We determined the expression profiles of microRNAs that are predicted to interact with the SNCA-3’UTR in isogenic iPSCs-derived dopaminergic and cholinergic neurons that are primarily involved in PD and DLB, respectively. In addition, we performed a deep-sequencing analysis of the SNCA-3’UTR using DNA samples from autopsy confirmed cases of PD, DLB, and matched normal controls, aiming to identify genetic variability in the 3’UTR that is associated, with the neuropathological diagnoses. We identified four highly conserved microRNA binding-sites in the SNCA 3’UTR, and observed a neuronal-type specific expression profile for each microRNA in the different isogenic iPSC-derived neurons, i.e. dopaminergic vs. cholinergic neurons. In the mature cholinergic neurons, the levels of the miR-140–3p.1 and miR-223–3p were dominant. While, in mature dopaminergic neurons miR-7–5p showed the highest expression by wide-margin, followed by miR-223–3p, and miR-153–3p. Furthermore, we found that the short-structural variant rs33988309-polyT was moderately and distinctively associated with DLB but not with PD. We suggest that neuronal type-specific mechanisms regulate SNCA gene expression and involve the contribution of both cis and trans acting factors. In support of a trans acting factor, our data showed differential expression of microRNAs in pathology-relevant cells proposing that different microRNAs regulate SNCA-mRNA expression levels in a neuronal-type specific manner. As an example of a cis acting factor, we discovered a genetic variant in the SNCA-3’UTR that specifically affects DLB risk, implying that distinct genetic variability in the SNCA gene may contribute to synucleinopathies in a pathology-specific manner.