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Genetic variability in the SNCA gene influences -synuclein levels in the blood and brain

Julia Fuchs^*,1, Ales Tichopad, Yulia Golub^*, Marita Munz^*, Katherine J. Schweitzer^*, Björn Wolf^*, Daniela Berg^*, Jakob C. Mueller^*, and Thomas Gasser^*,2

^* Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany;

Physiology Weihenstephan, Technical University Munich, Freising-Weihenstephan, Germany; and

Department of Behavioural Ecology and Evolutionary Genetics, Max Planck Institute for Ornithology, Starnberg (Seewiesen), Germany

²Correspondence: Hertie-Institute for Clinical Brain Research, Department of Neurodegenerative Diseases, Hoppe-Seyler Str. 3, 72076 Tübingen, Germany. E-mail: thomas.gasser{at}med.uni-tuebingen.de

Genetic variability in the promoter and 3' region of the SNCA gene coding -synuclein modulates the risk to develop sporadic Parkinson’s disease (PD). Whether this is mediated by regulating -synuclein expression levels remains unknown. Therefore, we analyzed levels of -synuclein in blood and human post mortem brain tissue including the substantia nigra using quantitative real-time reverse transcriptase-polymerase chain reaction and enzyme linked immunosorbent assay in vivo. Single nucleotide polymorphism (SNP) rs356219, a tagging SNP for a disease-associated haplotype in the 3' region of the SNCA gene, has a significant effect on SNCA mRNA levels in the substantia nigra and the cerebellum. Further, the "protective" genotype 259/259 of the PD-associated promoter repeat NACP-Rep1 is associated with lower protein levels in blood than genotypes 261/261, 259/261, and 259/263. In conclusion, we provide evidence that -synuclein levels are influenced by genetic variability in the promoter and 3' region of the SNCA gene in vivo.—Fuchs, J., Tichopad, A., Golub, Y., Munz, M., Schweitzer, K. J., Wolf, B., Berg, D., Mueller, J. C., Gasser, T. Genetic variability in the SNCA gene influences -synuclein levels in the blood and brain.

Key Words: Parkinson’s disease • SNP • NACP-Rep1 • substantia nigra • gene expression • real-time RT-PCR • ELISA