Human Molecular Genetics Advance Access published online on June 4, 2009
Human Molecular Genetics, doi:10.1093/hmg/ddp265
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Expansion of the Parkinson Disease-Associated SNCA-Rep1 Allele Up-Regulates Human 
-Synuclein in Transgenic Mouse Brain
1 Institute for Genome Sciences & Policy/Center for Human Genome Variation, Duke University, Durham, North Carolina, 27708; United States of America 2 Ottawa Health Research Institute/ Division of Neurosciences, University of Ottawa, Ottawa, Ontario, K1H 8M5; Canada. 3 National Genome Research Institute/Genetic Disease Research Branch, National Institute of Health, Bethesda, Maryland, 20892-4472; United States of America 4 Department of Biochemistry/Faculty of Medicine and Health Sciences, United Arab Emirates University, Al Ain; United Arab Emirates 5 Institute for Human Genetics/Division of Medical Genetics, University of California, San Francisco, California, 94143; United States of America 6 Department of Medicine/Division of Neurology, Duke University Medical Center, Durham, North Carolina, 27708; United States of America
* Corresponding author: Ornit Chiba-Falek Center for Human Genome Variation, Duke Institute for Genome Sciences and Policy, DUMC Box 91009, Duke University, Durham, North Carolina 27708, USA. Tel: 919 681 8001, Fax: 919 613-6448, E-mail: o.chibafalek{at}duke.edu
Received March 9, 2009; Revised May 26, 2009; Accepted June 1, 2009
Alpha-synuclein (SNCA) gene has been implicated in the development of rare forms of familial Parkinson disease (PD). Recently it was shown that an increase in SNCA copy numbers leads to elevated levels of wild-type SNCA-mRNA and protein and is sufficient to cause early-onset, familial PD. A critical question concerning the molecular pathogenesis of PD is what contributory role, if any, is played by the SNCA gene in sporadic PD. Expansion of SNCA-Rep1, an upstream, polymorphic microsatellite of the SNCA gene, is associated with elevated risk for sporadic PD. However, whether SNCA-Rep1 is the causal variant and the underlying mechanism its effect is mediated by, remained elusive. We report here the effects of three distinct SNCA-Rep1 variants in the brains of 72 mice transgenic for the entire human SNCA locus. Human SNCA-mRNA and protein levels were increased 1.7- and 1.25-fold, respectively, in homozygotes for the expanded, PD risk-conferring allele compared with homozygotes for the shorter, protective allele. When adjusting for the total SNCA-protein concentration (endogenous-mouse and transgenic-human) expressed in each brain, the expanded risk allele contributed 2.6-fold more SNCA steady-state than the shorter allele. Furthermore, targeted deletion of Rep1 resulted in the lowest human SNCA-mRNA and protein concentrations in murine brain. In contrast, the Rep1 effect was not observed in blood lysates from the same mice. These results demonstrate that Rep1 regulates human SNCA expression by enhancing its transcription in the adult nervous system and suggest that homozygosity for the expanded Rep1 allele may mimic locus multiplication, thereby elevating PD risk.