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

Kenneth D. Cronin, Dongliang Ge, Paul Manninger, Colton Linnertz, Anna Rossoshek, Bonnie M. Orrison, David J. Bernard, Omar Ali El-Agnaf, Michael G. Schlossmacher, Robert L. Nussbaum, Ornit Chiba-Falek

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Abstract

α-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.

Original languageEnglish
Pages (from-to)3274-3285
Number of pages12
JournalHuman Molecular Genetics
Volume18
Issue number17
DOIs
Publication statusPublished - 2009
Externally publishedYes

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Synucleins
Transgenic Mice
Parkinson Disease
Up-Regulation
Alleles
Brain
Homozygote
Messenger RNA
Genes
Microsatellite Repeats
Nervous System
Proteins

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

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 α-synuclein in transgenic mouse brain. Human Molecular Genetics, 18(17), 3274-3285. https://doi.org/10.1093/hmg/ddp265

Expansion of the Parkinson disease-associated SNCA-Rep1 allele upregulates human α-synuclein in transgenic mouse brain. / Cronin, Kenneth D.; Ge, Dongliang; Manninger, Paul; Linnertz, Colton; Rossoshek, Anna; Orrison, Bonnie M.; Bernard, David J.; Ali El-Agnaf, Omar; Schlossmacher, Michael G.; Nussbaum, Robert L.; Chiba-Falek, Ornit.

In: Human Molecular Genetics, Vol. 18, No. 17, 2009, p. 3274-3285.

Research output: Contribution to journalArticle

Cronin, KD, Ge, D, Manninger, P, Linnertz, C, Rossoshek, A, Orrison, BM, Bernard, DJ, Ali El-Agnaf, O, Schlossmacher, MG, Nussbaum, RL & Chiba-Falek, O 2009, 'Expansion of the Parkinson disease-associated SNCA-Rep1 allele upregulates human α-synuclein in transgenic mouse brain', Human Molecular Genetics, vol. 18, no. 17, pp. 3274-3285. https://doi.org/10.1093/hmg/ddp265
Cronin, Kenneth D. ; Ge, Dongliang ; Manninger, Paul ; Linnertz, Colton ; Rossoshek, Anna ; Orrison, Bonnie M. ; Bernard, David J. ; Ali El-Agnaf, Omar ; Schlossmacher, Michael G. ; Nussbaum, Robert L. ; Chiba-Falek, Ornit. / Expansion of the Parkinson disease-associated SNCA-Rep1 allele upregulates human α-synuclein in transgenic mouse brain. In: Human Molecular Genetics. 2009 ; Vol. 18, No. 17. pp. 3274-3285.
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AB - α-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.

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