title: Contribution of polymorphic variation of inositol hexakisphosphate kinase 3 (IP6K3) gene promoter to the susceptibility to late onset Alzheimer's disease.
abstract: Maintenance of electric potential and synaptic transmission are energetically demanding tasks that neuronal metabolism must continually satisfy. Inability to fulfil these energy requirements leads to the development of neurodegenerative disorders, including Alzheimer's disease. A prominent feature of Alzheimer's disease is in fact neuronal glucose hypometabolism. Thus understanding the fine control of energetic metabolism might help to understand neurodegenerative disorders. Recent research has indicated that a novel class of signalling molecules, the inositol pyrophosphates, act as energy sensors. They are able to alter the balance between mitochondrial oxidative phosphorylation and glycolytic flux, ultimately affecting the cellular level of ATP. The neuronal inositol pyrophosphate synthesis relies on the activity of the neuron enriched inositol hexakisphosphate kinase 3 (IP6K3) enzyme. To verify an involvement of inositol pyrophosphate signalling in neurodegenerative disorders, we performed tagging single nucleotide polymorphism (SNP) analysis of the IP6K3 gene in patients with familial and sporadic late onset Alzheimer's disease (LOAD). Two SNPs in the 5'-flanking promoter region of the IP6K3 gene were found to be associated with sporadic LOAD. Characterizing the functionality of the two polymorphisms by luciferase assay revealed that one of them (rs28607030) affects IP6K3 promoter activity, with the G allele showing an increased activity. As the same allele has a beneficial effect on disease risk, this may be related to upregulation of IP6K3 expression, with a consequent increase in inositol pyrophosphate synthesis. In conclusion, we provide the first evidence for a contribution of genetic variability in the IP6K3 gene to LOAD pathogenesis.
authors.affiliation: Department of Biology, Ecology and Earth Science, University of Calabria, Rende, CS, Italy.
authors.forename: Paolina
authors.initials: P
authors.lastname: Crocco
authors.affiliation: Medical Research Council Laboratory for Molecular Cell Biology, University College London, London, United Kingdom.
authors.forename: Adolfo
authors.initials: A
authors.lastname: Saiardi
authors.affiliation: Medical Research Council Laboratory for Molecular Cell Biology, University College London, London, United Kingdom.
authors.forename: Miranda S
authors.initials: MS
authors.lastname: Wilson
authors.affiliation: Regional Neurogenetic Centre, ASP CZ, Lamezia Terme, CZ, Italy.
authors.forename: Raffaele
authors.initials: R
authors.lastname: Maletta
authors.affiliation: Regional Neurogenetic Centre, ASP CZ, Lamezia Terme, CZ, Italy.
authors.forename: Amalia C
authors.initials: AC
authors.lastname: Bruni
authors.affiliation: Department of Biology, Ecology and Earth Science, University of Calabria, Rende, CS, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Passarino
authors.affiliation: Department of Biology, Ecology and Earth Science, University of Calabria, Rende, CS, Italy. Electronic address: pina.rose@unical.it.
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Rose
mesh_terms: D024506:5' Flanking Region; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000201:enzymology* / Q000209:etiology / Q000235:genetics*; D016022:Case-Control Studies; D002460:Cell Line; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D057809:HEK293 Cells; D006801:Humans; D066298:In Vitro Techniques; D015810:Linkage Disequilibrium; D008297:Male; D017856:Phosphotransferases (Phosphate Group Acceptor) / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic
chemical_list: D017856:Phosphotransferases (Phosphate Group Acceptor); C099438:inositol hexakisphosphate kinase
keywords: Alzheimer's disease; IP(7); IP6K3; Inositol pyrophosphate; Metabolism; SNP