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

Lidia Tagliafierro, Omolara Chinue Glenn, Madison E. Zamora, Thomas G. Beach, Randy L. Woltjer, Michael W. Lutz, Ornit Chiba-Falek

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1237-1250
Number of pages14
JournalAlzheimer's and Dementia
Volume13
Issue number11
DOIs
StatePublished - Nov 2017

Keywords

  • DLB
  • PD
  • SNCA
  • SNCA 3′ UTR
  • iPSC-derived neurons
  • miRNA

ASJC Scopus subject areas

  • Epidemiology
  • Health Policy
  • Developmental Neuroscience
  • Clinical Neurology
  • Geriatrics and Gerontology
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience

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