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The genetic contributions of SNCA and LRRK2 genes to Lewy Body pathology in Alzheimer's disease.

Publication ,  Journal Article
Linnertz, C; Lutz, MW; Ervin, JF; Allen, J; Miller, NR; Welsh-Bohmer, KA; Roses, AD; Chiba-Falek, O
Published in: Hum Mol Genet
September 15, 2014

The molecular genetic basis that leads to Lewy Body (LB) pathology in 15-20% of Alzheimer disease cases (LBV/AD) was largely unknown. Alpha-synuclein (SNCA) and Leucine-rich repeat kinase2 (LRRK2) have been implicated in the pathogenesis of Parkinson's disease (PD), the prototype of LB spectrum disorders. We tested the association of SNCA variants with LB pathology in AD. We then stratified the SNCA association analyses by LRRK2 genotype. We also investigated the expression regulation of SNCA and LRRK2 in relation to LB pathology. We evaluated the differences in SNCA-mRNA and LRRK2-mRNA levels as a function of LB pathology in the temporal cortex (TC) from autopsy-confirmed LBV/AD cases and AD controls. We further investigated the cis-effect of the LB pathology-associated genetic variants within the SNCA and LRRK2 loci on the mRNA expression of these genes. SNCA SNPs rs3857059 and rs2583988 showed significant associations with increased risk for LB pathology. When the analyses were stratified by LRRK2-rs1491923 genotype, the associations became stronger for both SNPs and an association was also observed with rs2619363. Expression analysis demonstrated that SNCA- and LRRK2-mRNA levels were significantly higher in TC from LBV/AD brains compared with AD controls. Furthermore, SNCA-mRNA expression level in the TC was associated with rs3857059; homozygotes for the minor allele showed significant higher expression. LRRK2-transcript levels were increased in carriers of rs1491923 minor allele. Our findings demonstrated that SNCA contributes to LB pathology in AD patients, possibly via interaction with LRRK2, and suggested that expression regulation of these genes may be the molecular basis underlying the observed LB associations.

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Published In

Hum Mol Genet

DOI

EISSN

1460-2083

Publication Date

September 15, 2014

Volume

23

Issue

18

Start / End Page

4814 / 4821

Location

England

Related Subject Headings

  • alpha-Synuclein
  • Temporal Lobe
  • Protein Serine-Threonine Kinases
  • Polymorphism, Single Nucleotide
  • Lewy Bodies
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • Humans
  • Genetics & Heredity
  • Genetic Variation
  • Genetic Association Studies
 

Citation

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Chicago
ICMJE
MLA
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Linnertz, C., Lutz, M. W., Ervin, J. F., Allen, J., Miller, N. R., Welsh-Bohmer, K. A., … Chiba-Falek, O. (2014). The genetic contributions of SNCA and LRRK2 genes to Lewy Body pathology in Alzheimer's disease. Hum Mol Genet, 23(18), 4814–4821. https://doi.org/10.1093/hmg/ddu196
Linnertz, Colton, Michael W. Lutz, John F. Ervin, Jawara Allen, Natalie R. Miller, Kathleen A. Welsh-Bohmer, Allen D. Roses, and Ornit Chiba-Falek. “The genetic contributions of SNCA and LRRK2 genes to Lewy Body pathology in Alzheimer's disease.Hum Mol Genet 23, no. 18 (September 15, 2014): 4814–21. https://doi.org/10.1093/hmg/ddu196.
Linnertz C, Lutz MW, Ervin JF, Allen J, Miller NR, Welsh-Bohmer KA, et al. The genetic contributions of SNCA and LRRK2 genes to Lewy Body pathology in Alzheimer's disease. Hum Mol Genet. 2014 Sep 15;23(18):4814–21.
Linnertz, Colton, et al. “The genetic contributions of SNCA and LRRK2 genes to Lewy Body pathology in Alzheimer's disease.Hum Mol Genet, vol. 23, no. 18, Sept. 2014, pp. 4814–21. Pubmed, doi:10.1093/hmg/ddu196.
Linnertz C, Lutz MW, Ervin JF, Allen J, Miller NR, Welsh-Bohmer KA, Roses AD, Chiba-Falek O. The genetic contributions of SNCA and LRRK2 genes to Lewy Body pathology in Alzheimer's disease. Hum Mol Genet. 2014 Sep 15;23(18):4814–4821.
Journal cover image

Published In

Hum Mol Genet

DOI

EISSN

1460-2083

Publication Date

September 15, 2014

Volume

23

Issue

18

Start / End Page

4814 / 4821

Location

England

Related Subject Headings

  • alpha-Synuclein
  • Temporal Lobe
  • Protein Serine-Threonine Kinases
  • Polymorphism, Single Nucleotide
  • Lewy Bodies
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • Humans
  • Genetics & Heredity
  • Genetic Variation
  • Genetic Association Studies