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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Elsevier
2005-04-01
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Series: | Neurobiology of Disease |
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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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issn | 1095-953X |
language | English |
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series | Neurobiology of Disease |
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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