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Expansion of the Parkinson disease-associated SNCA-Rep1 allele upregulates human alpha-synuclein in transgenic mouse brain.

Publication ,  Journal Article
Cronin, KD; Ge, D; Manninger, P; Linnertz, C; Rossoshek, A; Orrison, BM; Bernard, DJ; El-Agnaf, OMA; Schlossmacher, MG; Nussbaum, RL; Chiba-Falek, O
Published in: Hum Mol Genet
September 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. 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.

Duke Scholars

Published In

Hum Mol Genet

DOI

EISSN

1460-2083

Publication Date

September 1, 2009

Volume

18

Issue

17

Start / End Page

3274 / 3285

Location

England

Related Subject Headings

  • alpha-Synuclein
  • Up-Regulation
  • Polymorphism, Genetic
  • Parkinson Disease
  • Microsatellite Repeats
  • Mice, Transgenic
  • Mice
  • Male
  • Humans
  • Genetics & Heredity
 

Citation

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Cronin, K. D., Ge, D., Manninger, P., Linnertz, C., Rossoshek, A., Orrison, B. M., … Chiba-Falek, O. (2009). Expansion of the Parkinson disease-associated SNCA-Rep1 allele upregulates human alpha-synuclein in transgenic mouse brain. Hum Mol Genet, 18(17), 3274–3285. https://doi.org/10.1093/hmg/ddp265
Cronin, Kenneth D., Dongliang Ge, Paul Manninger, Colton Linnertz, Anna Rossoshek, Bonnie M. Orrison, David J. Bernard, et al. “Expansion of the Parkinson disease-associated SNCA-Rep1 allele upregulates human alpha-synuclein in transgenic mouse brain.Hum Mol Genet 18, no. 17 (September 1, 2009): 3274–85. https://doi.org/10.1093/hmg/ddp265.
Cronin KD, Ge D, Manninger P, Linnertz C, Rossoshek A, Orrison BM, et al. Expansion of the Parkinson disease-associated SNCA-Rep1 allele upregulates human alpha-synuclein in transgenic mouse brain. Hum Mol Genet. 2009 Sep 1;18(17):3274–85.
Cronin, Kenneth D., et al. “Expansion of the Parkinson disease-associated SNCA-Rep1 allele upregulates human alpha-synuclein in transgenic mouse brain.Hum Mol Genet, vol. 18, no. 17, Sept. 2009, pp. 3274–85. Pubmed, doi:10.1093/hmg/ddp265.
Cronin KD, Ge D, Manninger P, Linnertz C, Rossoshek A, Orrison BM, Bernard DJ, El-Agnaf OMA, Schlossmacher MG, Nussbaum RL, Chiba-Falek O. Expansion of the Parkinson disease-associated SNCA-Rep1 allele upregulates human alpha-synuclein in transgenic mouse brain. Hum Mol Genet. 2009 Sep 1;18(17):3274–3285.
Journal cover image

Published In

Hum Mol Genet

DOI

EISSN

1460-2083

Publication Date

September 1, 2009

Volume

18

Issue

17

Start / End Page

3274 / 3285

Location

England

Related Subject Headings

  • alpha-Synuclein
  • Up-Regulation
  • Polymorphism, Genetic
  • Parkinson Disease
  • Microsatellite Repeats
  • Mice, Transgenic
  • Mice
  • Male
  • Humans
  • Genetics & Heredity