Abstract
The SNCA intronic single nucleotide polymorphism (SNP), rs356168, has been associated with Parkinson’s disease (PD) in large genome wide association studies (GWAS). Recently, the PD-risk allele, rs356168-G was shown to increase SNCA-mRNA expression using genome edited human induced pluripotent stem cells (iPSC)-derived neurons. In this study, as means of validation, we tested the effect of rs356168 on total SNCA-mRNA levels using brain tissues, temporal and frontal cortex, from healthy control donors. Carriers of the rs356168-G allele demonstrated a borderline significant decrease of SNCA-mRNA levels in temporal brain tissues (p = 0.02) compared to individuals homozygous for the ‘A’ allele. Similar trend, but weak, was observed in the analysis of frontal cortex samples, however, this analysis did not reach statistical significance. These results conflict with the recently reported effect of SNCA SNP rs356168 described above. Our study conveys the need to carefully interpret the precise molecular mechanism by which rs356168, or another tightly linked variant, affects the regulation of SNCA expression. The regulatory mechanisms that contribute to the observed associations between PD and the SNCA-3′ linkage disequilibrium region warrant further investigations.
Highlights
The analyses were performed using post-mortem matched brain tissues from unaffected individuals to directly assess the genetic contribution to the regulation of SNCA expression, avoiding other confounding factors arising from the neurodegeneration associated with Parkinson’s disease (PD)
We studied the association of a PDassociated single nucleotide polymorphism (SNP) with total SNCA-mRNA levels using an assay with best coverage for SNCA transcript forms
We demonstrated that individual carriers of the PD-risk allele rs356168-G exhibited decreased SNCA-mRNA levels in the temporal cortex compared to homozygous of the PD-‘protective’ allele (‘AA’)
Summary
Genetic associations of the SNCA gene have been reported with several neurodegenerative disorders that share the common pathology of Lewy bodies (LB), including familial and nonfamilial Parkinson’s disease (PD) (Pals et al, 2004; Mueller et al, 2005; Maraganore et al, 2006; Mizuta et al, 2006; Ross et al, 2007; Winkler et al, 2007; Myhre et al, 2008; Pankratz et al, 2009; Satake et al, 2009; Simon-Sanchez et al, 2009, 2011; Edwards et al, 2010; Mata et al, 2010; Spencer et al, 2011). The precise genetic variants within the SNCA gene that contribute to non-Mendelian PD and related synucleinopathies, and their molecular mechanisms of action, are largely unknown. Various technologies and approaches including in vitro and in vivo model systems are being developed continuously to advance this field of inquiry. One of these approaches is eQTL analysis using tissues relevant to the studied disease
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