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Genetic regulation of alpha-synuclein mRNA expression in various human brain tissues.

Publication ,  Journal Article
Linnertz, C; Saucier, L; Ge, D; Cronin, KD; Burke, JR; Browndyke, JN; Hulette, CM; Welsh-Bohmer, KA; Chiba-Falek, O
Published in: PLoS One
October 16, 2009

Genetic variability across the SNCA locus has been repeatedly associated with susceptibility to sporadic Parkinson's disease (PD). Accumulated evidence emphasizes the importance of SNCA dosage and expression levels in PD pathogenesis. However whether genetic variability in the SNCA gene modulates the risk to develop sporadic PD via regulation of SNCA expression remained elusive. We studied the effect of PD risk-associated variants at SNCA 5' and 3'regions on SNCA-mRNA levels in vivo in 228 human brain samples from three structures differentially vulnerable to PD pathology (substantia-nigra, temporal- and frontal-cortex) obtained from 144 neurologically normal cadavers. The extensively characterized PD-associated promoter polymorphism, Rep1, had an effect on SNCA-mRNA levels. Homozygous genotype of the 'protective', Rep1-259 bp allele, was associated with lower levels of SNCA-mRNA relative to individuals that carried at least one copy of the PD-risk associated alleles, amounting to an average decrease of approximately 40% and >50% in temporal-cortex and substantia-nigra, respectively. Furthermore, SNPs tagging the SNCA 3'-untranslated-region also showed effects on SNCA-mRNA levels in both the temporal-cortex and the substantia-nigra, although, in contrast to Rep1, the 'decreased-risk' alleles were correlated with increased SNCA-mRNA levels. Similar to Rep1 findings, no difference in SNCA-mRNA level was seen with different SNCA 3'SNP alleles in the frontal-cortex, indicating there is brain-region specificity of the genetic regulation of SNCA expression. We provide evidence for functional consequences of PD-associated SNCA gene variants in disease relevant brain tissues, suggesting that genetic regulation of SNCA expression plays an important role in the development of the disease.

Duke Scholars

Published In

PLoS One

DOI

EISSN

1932-6203

Publication Date

October 16, 2009

Volume

4

Issue

10

Start / End Page

e7480

Location

United States

Related Subject Headings

  • alpha-Synuclein
  • Tissue Distribution
  • Temporal Lobe
  • Substantia Nigra
  • RNA, Messenger
  • Pons
  • Middle Aged
  • Mesencephalon
  • Male
  • Humans
 

Citation

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Linnertz, C., Saucier, L., Ge, D., Cronin, K. D., Burke, J. R., Browndyke, J. N., … Chiba-Falek, O. (2009). Genetic regulation of alpha-synuclein mRNA expression in various human brain tissues. PLoS One, 4(10), e7480. https://doi.org/10.1371/journal.pone.0007480
Linnertz, Colton, Laura Saucier, Dongliang Ge, Kenneth D. Cronin, James R. Burke, Jeffrey N. Browndyke, Christine M. Hulette, Kathleen A. Welsh-Bohmer, and Ornit Chiba-Falek. “Genetic regulation of alpha-synuclein mRNA expression in various human brain tissues.PLoS One 4, no. 10 (October 16, 2009): e7480. https://doi.org/10.1371/journal.pone.0007480.
Linnertz C, Saucier L, Ge D, Cronin KD, Burke JR, Browndyke JN, et al. Genetic regulation of alpha-synuclein mRNA expression in various human brain tissues. PLoS One. 2009 Oct 16;4(10):e7480.
Linnertz, Colton, et al. “Genetic regulation of alpha-synuclein mRNA expression in various human brain tissues.PLoS One, vol. 4, no. 10, Oct. 2009, p. e7480. Pubmed, doi:10.1371/journal.pone.0007480.
Linnertz C, Saucier L, Ge D, Cronin KD, Burke JR, Browndyke JN, Hulette CM, Welsh-Bohmer KA, Chiba-Falek O. Genetic regulation of alpha-synuclein mRNA expression in various human brain tissues. PLoS One. 2009 Oct 16;4(10):e7480.

Published In

PLoS One

DOI

EISSN

1932-6203

Publication Date

October 16, 2009

Volume

4

Issue

10

Start / End Page

e7480

Location

United States

Related Subject Headings

  • alpha-Synuclein
  • Tissue Distribution
  • Temporal Lobe
  • Substantia Nigra
  • RNA, Messenger
  • Pons
  • Middle Aged
  • Mesencephalon
  • Male
  • Humans