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.
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.
Giacomello
Marta
M
Department of Biomedical Sciences, University of Padova, Via G. Colombo, 3, 35121 Padova, Italy.
Barbiero
Laura
L
Zatti
Giancarlo
G
Squitti
Rosanna
R
Binetti
Giuliano
G
Pozzan
Tullio
T
Fasolato
Cristina
C
Ghidoni
Roberta
R
Pizzo
Paola
P
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
D008565:Membrane Proteins; C508861:PSEN2 protein, human; D053766:Presenilin-2; D002118:Calcium