Abstract
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.
Highlights
Alpha-synuclein (SNCA) (Ensembl: ENSG00000145335; OMIM, Online Mendelian Inheritance in Man: MIM 163890) was the first gene found to be involved in Parkinson’s disease (PD[MIM 168600])
The average SNCA-mRNA fold levels observed in the frontal cortex samples was approximately 50% less from the average SNCA-mRNA fold levels detected in the temporal cortex and in the midbrain including substantia nigra (SN) of the same individuals
We were able to carry out a direct comparison of all three brain regions in 7 cadavers from whom all brain regions were available, showing that the average fold expression levels of SNCA-mRNA are similar in midbrain including SN and temporal cortex and nearly twice the average fold levels observed in the frontal cortex (Figure 1)
Summary
Alpha-synuclein (SNCA) (Ensembl: ENSG00000145335; OMIM, Online Mendelian Inheritance in Man: MIM 163890) was the first gene found to be involved in Parkinson’s disease (PD[MIM 168600]). Duplications of the wild-type SNCA gene result in a 1.5-fold elevation of SNCA expression and a slightly later onset of heritable PD that is characterized by a lower penetrance rate and a ‘milder’ phenotype than for the triplication [6,7,8,9], demonstrating the dose-dependent effect of SNCA on disease presentation. Elevated levels of SNCA-mRNA have been reported in midbrain tissues [12] and in individual substantia nigra dopaminergic neurons from sporadic PD post mortem brains compared to controls[13]. These observations emphasize the importance of SNCA dosage and expression levels in PD pathogenesis
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