Human Molecular Genetics Advance Access originally published online on June 4, 2009
Human Molecular Genetics 2009 18(17):3274-3285; doi:10.1093/hmg/ddp265
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Expansion of the Parkinson disease-associated SNCA-Rep1 allele upregulates human 
-synuclein in transgenic mouse brain
1 Center for Human Genome Variation, Institute for Genome Sciences and Policy, Duke University, Durham, NC 27708, USA 2 Division of Neurosciences, Ottawa Health Research Institute, University of Ottawa, Ottawa, Ontario, Canada K1H 8M5 3 Genetic Disease Research Branch, National Human Genome Research Institute, National Institute of Health, Bethesda, MD 20892-4472, USA 4 Department of Biochemistry, Faculty of Medicine and Health Sciences, United Arab Emirates University, Al Ain, UAE 5 Division of Medical Genetics, Institute for Human Genetics, University of California, San Francisco, CA 94143, USA 6 Division of Neurology, Department of Medicine, Duke University Medical Center, Durham, NC 27708, USA
* To whom correspondence should be addressed at: Center for Human Genome Variation, Duke Institute for Genome Sciences and Policy, DUMC Box 91009, Duke University, Durham, NC 27708, USA. Tel: +1 9196818001; Fax: +1 9196136448; Email: o.chibafalek{at}duke.edu
Received March 9, 2009; Accepted June 1, 2009
-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. The 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 with which 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 to the 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.