The cis-regulatory effect of an Alzheimer's disease-associated poly-T locus on expression of TOMM40 and apolipoprotein E genes.

Abstract

BACKGROUND:

We investigated the genomic region spanning the Translocase of the Outer Mitochondrial Membrane 40-kD (TOMM40) and Apolipoprotein E (APOE) genes, that has been associated with the risk and age of onset of late-onset Alzheimer's disease (LOAD) to determine whether a highly polymorphic, intronic poly-T within this region (rs10524523; hereafter, 523) affects expression of the APOE and TOMM40 genes. Alleles of this locus are classified as S, short; L, long; and VL, very long based on the number of T residues.

METHODS:

We evaluated differences in APOE messenger RNA (mRNA) and TOMM40 mRNA levels as a function of the 523 genotype in two brain regions from APOE ε3/ε3 white autopsy-confirmed LOAD cases and normal controls. We further investigated the effect of the 523 locus in its native genomic context using a luciferase expression system.

RESULTS:

The expression of both genes was significantly increased with disease. Mean expression of APOE and TOMM40 mRNA levels were higher in VL homozygotes compared with S homozygotes in the temporal and occipital cortexes from normal and LOAD cases. Results of a luciferase reporter system were consistent with the human brain mRNA analysis; the 523 VL poly-T resulted in significantly higher expression than the S poly-T. Although the effect of poly-T length on reporter expression was the same in HepG2 hepatoma and SH-SY5Y neuroblastoma cells, the magnitude of the effect was greater in the neuroblastoma than in the hepatoma cells, which implies tissue-specific modulation of the 523 poly-T.

CONCLUSIONS:

These results suggest that the 523 locus may contribute to LOAD susceptibility by modulating the expression of TOMM40 and/or APOE transcription.

• Authors: Colton Linnertz, Lauren Anderson, William Gottschalk, Donna Crenshaw, Michael W Lutz, Jawara Allen, Sunita Saith, Mirta Mihovilovic, James R Burke, Kathleen A Welsh-Bohmer, Allen D Roses, Ornit Chiba-Falek
• Journal: Alzheimer's & dementia : the journal of the Alzheimer's Association (Alzheimers Dement) Vol. 10 Issue 5 Pg. 541-51 (Sep 2014) ISSN: 1552-5279 [Electronic] United States
• PMID: 24439168 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

Chemical References

• Apolipoproteins E
• Membrane Transport Proteins
• Mitochondrial Precursor Protein Import Complex Proteins
• RNA, Messenger
• TOMM40 protein, human

Topics

• Age of Onset
• Aged
• Alzheimer Disease (genetics, metabolism)
• Apolipoproteins E (genetics, metabolism)
• Cell Line, Tumor
• Female
• Gene Expression Regulation
• Genetic Predisposition to Disease
• Genotype
• Hep G2 Cells
• Humans
• Male
• Membrane Transport Proteins (genetics, metabolism)
• Mitochondrial Precursor Protein Import Complex Proteins
• Occipital Lobe (metabolism)
• Polymorphism, Genetic
• RNA, Messenger (genetics, metabolism)
• Temporal Lobe (metabolism)
• Transfection