title: The Genetic Variability of UCP4 Affects the Individual Susceptibility to Late-Onset Alzheimer's Disease and Modifies the Disease's Risk in APOE-ɛ4 Carriers.
abstract: Uncoupling proteins (UCPs) are a group of five mitochondrial inner membrane transporters with a tissue specific expression that uncouple biofuel oxidation from ATP synthesis and function as regulators of energy homeostasis and antioxidants. Previous data suggested that neuronal UCPs (UCP2, UCP4, and UCP5) can directly influence synaptic plasticity, neurotransmission, and neurodegenerative processes, and have a crucial role in the function and protection of the central nervous system. In fact, it has been observed that the expression of neuronal UCPs significantly decreases in Alzheimer's disease (AD) patients. Here we analyzed the variability of UCP2, -3, -4, and 5 genes in sporadic and familial cases (n = 465) of late-onset AD (LOAD) with respect to healthy controls (n = 442). We showed that a genetic variant in the human UCP4, rs9472817, not only significantly affects the individual susceptibility to LOAD, but also modulates the effect of APOE-ɛ4 on AD risk. In fact, rs9472817-C allele was significantly more frequent in both groups of patients with respect to the control group (p = 6.934*10-4 for familial and p = 1.033*10-3 for sporadic cases). In addition, gene-gene interaction analysis revealed that the effect of APOE-ɛ4 allele on LOAD risk was doubled in homozygote CC subjects; conversely, the risk conferred by the APOE-ɛ4 allele was annulled in subjects with two copies of the G allele. Our findings are further evidence that the efficiency in mitochondrial energy metabolism and oxidative stress are important factors in AD pathogenesis.
authors.affiliation: Department of Biology, Ecology and Earth Science, University of Calabria, Rende (CS), Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Montesanto
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: Regional Neurogenetic Centre, ASP CZ, Lamezia Terme (CZ), Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Anfossi
authors.affiliation: Regional Neurogenetic Centre, ASP CZ, Lamezia Terme (CZ), Italy.
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Smirne
authors.affiliation: Regional Neurogenetic Centre, ASP CZ, Lamezia Terme (CZ), Italy.
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Puccio
authors.affiliation: Regional Neurogenetic Centre, ASP CZ, Lamezia Terme (CZ), Italy.
authors.forename: Rosanna
authors.initials: R
authors.lastname: Colao
authors.affiliation: Regional Neurogenetic Centre, ASP CZ, Lamezia Terme (CZ), Italy.
authors.forename: Raffaele
authors.initials: R
authors.lastname: Maletta
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: 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: Giuseppina
authors.initials: G
authors.lastname: Rose
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000000981:diagnostic imaging / Q000235:genetics*; D053327:Apolipoprotein E4 / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D008297:Male; D008609:Mental Status Schedule; D000071245:Mitochondrial Uncoupling Proteins / Q000235:genetics*; D059906:Neuroimaging; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*
chemical_list: D053327:Apolipoprotein E4; D000071245:Mitochondrial Uncoupling Proteins; C117577:SLC25A27 protein, human
keywords: APOE; Alzheimer’s disease; UCP4; genetic risk; mitochondria; neurodegeneration; uncoupling proteins