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Biochemical Studies of Poly-T Variants in the Alzheimer's Disease Associated TOMM40 Gene

Article type: Research Article

Authors: Hedskog, Louisea | Brohede, Jespera | Wiehager, Birgittaa | Pinho, Catarina Moreirab | Revathikumar, Priyaa | Lilius, Lenaa | Glaser, Elzbietab | Graff, Carolinea; c | Karlström, Helenaa | Ankarcrona, Mariaa; *

Affiliations: [a] KI-Alzheimer's Disease Research Center, Karolinska Institutet, Department of Neurobiology, Care Sciences and Society (NVS), Stockholm, Sweden | [b] Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden | [c] Genetics Unit, Department of Geriatric Medicine, Karolinska University Hospital, Huddinge, Stockholm, Sweden

Correspondence: [*] Correspondence to: Maria Ankarcrona, KI-Alzheimer's Disease Research Center, Karolinska Institutet, Department of Neurobiology, Care Sciences and Society (NVS), Novum 5th floor, SE-141 86 Stockholm, Sweden. Tel.: +46 8 58583617; Fax: +46 8 58583610; E-mail: [email protected].

Keywords: Human fibroblast cell line, late-onset Alzheimer's disease (LOAD), mitochondria, TOMM40

DOI: 10.3233/JAD-2012-120580

Journal: Journal of Alzheimer's Disease, vol. 31, no. 3, pp. 527-536, 2012

Accepted 17 April 2012
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Published: 22 August 2012
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Abstract

The apolipoprotein E (APOE) gene remains the most strongly established risk factor for late onset Alzheimer's disease (LOAD). Recently the gene, TOMM40, which is in linkage disequilibrium with APOE, was identified to be associated with LOAD in genome-wide association studies. One of the identified polymorphisms in TOMM40 is rs10524523, which is located in intron 6 and composed of thymidine repeats varying between 14 to 36 base-pairs in length. Reported results are contradictory in regard to the very long poly-T variant that has been associated with both increased and decreased risk of LOAD. Our study aimed to elucidate the functional implication of rs10524523 in an in vitro model of human fibroblast cells obtained from cognitively healthy APOE ε3/ε4 carriers harboring very long or short poly-T variants coupled to their APOE ε3 allele. We have studied (i) expression levels of TOM40 protein and mRNA, (ii) TOM40 mRNA splicing, and (iii) mitochondrial function and morphology; and we have found no significant differences in regards to very long or short poly-T variant.

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