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Genetic variability across the  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 whether genetic variability in the  SNCA  gene modulates the risk to develop sporadic PD via regulation of  SNCA  expression remained elusive. We studied the effect of PD risk-associated variants at  SNCA  5′ and 3′regions on  SNCA -mRNA levels  in vivo  in 228 human brain samples from three structures differentially vulnerable to PD pathology (substantia-nigra, temporal- and frontal-cortex) obtained from 144 neurologically normal cadavers. The extensively characterized PD-associated promoter polymorphism, Rep1, had an effect on  SNCA -mRNA levels. Homozygous genotype of the ‘protective’, Rep1-259 bp allele, was associated with lower levels of  SNCA -mRNA relative to individuals that carried at least one copy of the PD-risk associated alleles, amounting to an average decrease of ∼40% and >50% in temporal-cortex and substantia-nigra, respectively. Furthermore, SNPs tagging the  SNCA  3′-untranslated-region also showed effects on  SNCA -mRNA levels in both the temporal-cortex and the substantia-nigra, although, in contrast to Rep1, the ‘decreased-risk’ alleles were correlated with increased  SNCA -mRNA levels. Similar to Rep1 findings, no difference in  SNCA- mRNA level was seen with different  SNCA  3′SNP alleles in the frontal-cortex, indicating there is brain-region specificity of the genetic regulation of  SNCA  expression. We provide evidence for functional consequences of PD-associated  SNCA  gene variants in disease relevant brain tissues, suggesting that genetic regulation of  SNCA  expression plays an important role in the development of the disease.

Genetic Regulation of α-Synuclein mRNA Expression in Various Human Brain Tissues