Familial Alzheimer's disease-associated presenilin 1 mutants promote γ-secretase cleavage of STIM1 to impair store-operated Ca2+ entry.
Some forms of familial Alzheimer's disease (FAD) are caused by mutations in presenilins (PSs), catalytic components of a γ-secretase complex that cleaves target proteins, including amyloid precursor protein (APP). Calcium (Ca(2+)) dysregulation in cells with these FAD-causing PS mutants has been attributed to attenuated store-operated Ca(2+) entry [SOCE; also called capacitative Ca(2+) entry (CCE)]. CCE occurs when STIM1 detects decreases in Ca(2+) in the endoplasmic reticulum (ER) and activates ORAI channels to replenish Ca(2+) stores in the ER. We showed that CCE was attenuated by PS1-associated γ-secretase activity. Endogenous PS1 and STIM1 interacted in human neuroblastoma SH-SY5Y cells, patient fibroblasts, and mouse primary cortical neurons. Forms of PS1 with FAD-associated mutations enhanced γ-secretase cleavage of the STIM1 transmembrane domain at a sequence that was similar to the γ-secretase cleavage sequence of APP. Cultured hippocampal neurons expressing mutant PS1 had attenuated CCE that was associated with destabilized dendritic spines, which were rescued by either γ-secretase inhibition or overexpression of STIM1. Our results indicate that γ-secretase activity may physiologically regulate CCE by targeting STIM1 and that restoring STIM1 may be a therapeutic approach in AD.
School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, China.
Benjamin Chun-Kit
BC
Tong
School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, China.
Claire Shuk-Kwan
CS
Lee
School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, China.
Wing-Hei
WH
Cheng
School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, China. State Key Laboratory of Brain and Cognitive Sciences, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, China.
Kwok-On
KO
Lai
Departments of Physiology and Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
J Kevin
JK
Foskett
School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, China. State Key Laboratory of Brain and Cognitive Sciences, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, China. HKU-Shenzhen Institute of Research and Innovation, Shenzhen, Guangdong, China. kingho.cheung@hku.hk.
King-Ho
KH
Cheung
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D045744:Cell Line, Tumor; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D000071737:Stromal Interaction Molecule 1 / Q000235:genetics / Q000378:metabolism*
D009363:Neoplasm Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1; C000607793:Psen1 protein, rat; C103530:STIM1 protein, human; C100757:Stim1 protein, mouse; C518857:Stim1 protein, rat; D000071737:Stromal Interaction Molecule 1; C580804:presenilin 1, mouse; D053829:Amyloid Precursor Protein Secretases; D002118:Calcium