Pan-SNCA vs. isoform-selective antisense oligonucleotide knockdown of SNCA-dIRE in SK-MEL-28 cells (ATF4 follow-up)

While rare genetic variants in SNCA can cause neuronal aSyn accumulation and neurodegeneration in some cases of familial disease, the molecular mechanisms driving SNCA associated risk in idiopathic Parkinson's disease remain elusive. The canonical SNCA mRNA transcript contains a 5'UTR iron response element (IRE) that regulates translation based on cellular iron content.

In this study we investigate an alternative transcript isoform lacking this element (dIRE) by evaluating SNCA transcript profiles across neuronal cell lines and post-mortem brain datasets. We show evidence that elevated dIRE expression correlates with increased disease risk in genome-wide association studies and is preferentially expressed in dopaminergic cells. Further, we show that dIRE expression may depend on transcription start site selection controlled by CpG methylation overlapping a known transcription factor binding site, where a PD associated risk haplotype exhibits lower methylation of this CpG site.