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 M23...

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Main Authors: Marta Giacomello, Laura Barbiero, Giancarlo Zatti, Rosanna Squitti, Giuliano Binetti, Tullio Pozzan, Cristina Fasolato, Roberta Ghidoni, Paola Pizzo
Format: Article
Language:English
Published: Elsevier 2005-04-01
Series:Neurobiology of Disease
Subjects:
Online Access:http://www.sciencedirect.com/science/article/pii/S0969996104002682
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author Marta Giacomello
Laura Barbiero
Giancarlo Zatti
Rosanna Squitti
Giuliano Binetti
Tullio Pozzan
Cristina Fasolato
Roberta Ghidoni
Paola Pizzo
author_facet Marta Giacomello
Laura Barbiero
Giancarlo Zatti
Rosanna Squitti
Giuliano Binetti
Tullio Pozzan
Cristina Fasolato
Roberta Ghidoni
Paola Pizzo
author_sort Marta Giacomello
collection DOAJ
description 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.
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spelling doaj.art-c848f718e8c54aa7b7f95f9a6885b27f2022-12-21T23:21:39ZengElsevierNeurobiology of Disease1095-953X2005-04-01183638648Reduction of Ca2+ stores and capacitative Ca2+ entry is associated with the familial Alzheimer's disease presenilin-2 T122R mutation and anticipates the onset of dementiaMarta Giacomello0Laura Barbiero1Giancarlo Zatti2Rosanna Squitti3Giuliano Binetti4Tullio Pozzan5Cristina Fasolato6Roberta Ghidoni7Paola Pizzo8Department of Biomedical Sciences, University of Padova, Via G. Colombo, 3, 35121 Padova, ItalyNeurobiology Lab-Memory Clinic, IRCCS “Centro San Giovanni di Dio-FBF”-AFaR, Via Pilastroni 4, 25123 Brescia, ItalyDepartment of Biomedical Sciences, University of Padova, Via G. Colombo, 3, 35121 Padova, ItalyDepartment of Neuroscience, AFaR-Ospedale Fatebenefratelli, Rome, ItalyNeurobiology Lab-Memory Clinic, IRCCS “Centro San Giovanni di Dio-FBF”-AFaR, Via Pilastroni 4, 25123 Brescia, ItalyDepartment of Biomedical Sciences, University of Padova, Via G. Colombo, 3, 35121 Padova, ItalyDepartment of Biomedical Sciences, University of Padova, Via G. Colombo, 3, 35121 Padova, ItalyNeurobiology Lab-Memory Clinic, IRCCS “Centro San Giovanni di Dio-FBF”-AFaR, Via Pilastroni 4, 25123 Brescia, Italy; Corresponding authors. R. Ghidoni is to be contacted at Fax: +39 30 3533513. P. Pizzo, Fax: +39 49 8276049.Department of Biomedical Sciences, University of Padova, Via G. Colombo, 3, 35121 Padova, Italy; Corresponding authors. R. Ghidoni is to be contacted at Fax: +39 30 3533513. P. Pizzo, Fax: +39 49 8276049.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.http://www.sciencedirect.com/science/article/pii/S0969996104002682PresenilinAlzheimer's diseaseCa2+ homeostasisCapacitative Ca2+ entryMonozygotic twinsFibroblasts
spellingShingle Marta Giacomello
Laura Barbiero
Giancarlo Zatti
Rosanna Squitti
Giuliano Binetti
Tullio Pozzan
Cristina Fasolato
Roberta Ghidoni
Paola Pizzo
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
Neurobiology of Disease
Presenilin
Alzheimer's disease
Ca2+ homeostasis
Capacitative Ca2+ entry
Monozygotic twins
Fibroblasts
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
title_full 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
title_fullStr 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
title_full_unstemmed 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
title_short 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
title_sort 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
topic Presenilin
Alzheimer's disease
Ca2+ homeostasis
Capacitative Ca2+ entry
Monozygotic twins
Fibroblasts
url http://www.sciencedirect.com/science/article/pii/S0969996104002682
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