The effect of SNCA 3' region on the levels of SNCA-112 splicing variant.

Genetic variability at the 3' region of SNCA locus has been repeatedly associated with susceptibility to sporadic Parkinson's disease (PD). Accumulated evidence emphasizes the importance of SNCA dosage and expression levels in PD pathogenesis. However, the mechanism through which the 3' region of SNCA gene modulates the risk to develop sporadic PD remained elusive. We studied the effect of PD risk-associated variants at SNCA 3' regions on SNCA112-mRNA (exon 5 in-frame skipping) levels in vivo in 117 neuropathologically normal, human brain frontal cortex samples. SNPs tagging the SNCA 3' showed significant effects on the relative levels of SNCA112-mRNA from total SNCA transcripts levels. The "risk" alleles were correlated with increased expression ratio of SNCA112-mRNA from total. We provide evidence for functional consequences of PD-associated SNCA gene variants at the 3' region, suggesting that genetic regulation of SNCA splicing plays an important role in the development of the disease. Further studies to determine the definite functional variant/s within SNCA 3'and to establish their association with PD pathology are necessary.