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

Paola Pizzo¹  Marta Giacomello²  Cristina Fasolato²  Giancarlo Zatti²  Tullio Pozzan²  Rosanna Squitti³  Roberta Ghidoni⁴  Laura Barbiero⁴  Giuliano Binetti⁴ 

[1] Corresponding authors. R. Ghidoni is to be contacted at Fax: [phone]. P. Pizzo, Fax: [phone].;Department of Biomedical Sciences, University of Padova, Via G. Colombo, 3, 35121 Padova, Italy;Department of Neuroscience, AFaR-Ospedale Fatebenefratelli, Rome, Italy;Neurobiology Lab-Memory Clinic, IRCCS “Centro San Giovanni di Dio-FBF”-AFaR, Via Pilastroni 4, 25123 Brescia, Italy;

关键词: Presenilin;    Alzheimer's disease;    Ca2+ homeostasis;    Capacitative Ca2+ entry;    Monozygotic twins;    Fibroblasts;   

DOI  :  

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown