title: Reduction of Ca2+ stores and capacitative Ca2+ entry is associated with the familial Alzheimer's disease presenilin-2 T122R mutation and anticipates the onset of dementia.
abstract: Mutations in the presenilin genes PS1 and PS2, the major cause of familial Alzheimer's disease (FAD), are associated with alterations in Ca2+ signalling. In contrast to the majority of FAD-linked PS1 mutations, which cause an overload of intracellular Ca2+ pools, the FAD-linked PS2 mutation M239I reduces Ca2+ release from intracellular stores [Zatti, G., Ghidoni, R., Barbiero, L., Binetti, G., Pozzan, T., Fasolato, C., Pizzo, P., 2004. The presenilin 2 M239I mutation associated with Familial Alzheimer's Disease reduces Ca2+ release from intracellular stores. Neurobiol. Dis. 15/2, 269-278]. We here show that in human FAD fibroblasts another PS2 mutation (T122R) reduces both Ca2+ release and capacitative Ca2+ entry. The observation, done in two monozygotic twins, is of note since only one of the subjects showed overt signs of disease at the time of biopsy whereas the other one developed the disease 3 years later. This finding indicates that Ca2+ dysregulation anticipates the onset of dementia. A similar Ca2+ alteration occurred in HeLa and HEK293 cells transiently expressing PS2-T122R. Based on these data, the "Ca2+ overload" hypothesis in AD pathogenesis is here discussed and reformulated.
authors.affiliation: Department of Biomedical Sciences, University of Padova, Via G. Colombo, 3, 35121 Padova, Italy.
authors.forename: Marta
authors.initials: M
authors.lastname: Giacomello
authors.forename: Laura
authors.initials: L
authors.lastname: Barbiero
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Zatti
authors.forename: Rosanna
authors.initials: R
authors.lastname: Squitti
authors.forename: Giuliano
authors.initials: G
authors.lastname: Binetti
authors.forename: Tullio
authors.initials: T
authors.lastname: Pozzan
authors.forename: Cristina
authors.initials: C
authors.lastname: Fasolato
authors.forename: Roberta
authors.initials: R
authors.lastname: Ghidoni
authors.forename: Paola
authors.initials: P
authors.lastname: Pizzo
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism*; D002118:Calcium / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D020013:Calcium Signaling / Q000235:genetics*; D002460:Cell Line; D003704:Dementia / Q000235:genetics / Q000378:metabolism; D005260:Female; D006367:HeLa Cells; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism*; D008875:Middle Aged; D017354:Point Mutation; D053766:Presenilin-2; D014430:Twins, Monozygotic / Q000235:genetics / Q000378:metabolism
chemical_list: D008565:Membrane Proteins; C508861:PSEN2 protein, human; D053766:Presenilin-2; D002118:Calcium