Identification of a Nuclear Respiratory Factor 1 Recognition Motif in the Apolipoprotein E Variant APOE4 linked to Alzheimer’s Disease

• Published in: Scientific reports Vol. 7; no. 1; p. 40668
• Main Authors: Urfer-Buchwalder, Anne, Urfer, Roman
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 17.01.2017; Nature Publishing Group
• Subjects: 631/208/200; 631/337/572/2102; 631/378/1689; 631/378/2583; Alzheimer's disease; Apolipoprotein E4; Apolipoproteins; Binding sites; Deoxyribonucleic acid; DNA; E protein; Enhancers; Environmental factors; Etiology; Gene polymorphism; Health risk assessment; Humanities and Social Sciences; multidisciplinary; Neurodegeneration; Neurodegenerative diseases; Risk factors; Science; Science (multidisciplinary); Single-nucleotide polymorphism
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep40668

Alzheimer’s disease affects tens of millions of people worldwide and its prevalence continues to rise. It is caused by a combination of a subject’s heredity, environment, lifestyle, and medical condition. The most significant genetic risk factor for late onset Alzheimer’s disease is a variant of the apolipoprotein E gene, APOE4. Here we show that the single nucleotide polymorphism rs429358 that defines APOE4 is located in a short sequence motif repeated several times within exon 4 of apolipoprotein E, reminiscent of the structure of transcriptional enhancers. A JASPAR database search predicts that the T to C transition in rs429358 generates a binding motif for nuclear respiratory factor NRF1. This site appears to be part of a binding site cluster for this transcription factor on exon 4 of APOE. This de novo NRF1 binding site has therefore the potential to affect the expression of multiple genes in its genomic vicinity. Our in silico analysis, suggesting a novel function for APOE4 at the DNA level, offers a potential mechanism for the observed tissue specific neurodegeneration and the role of environmental factors in Alzheimer’s disease etiology.