Journal
SCIENCE SIGNALING
Volume 9, Issue 444, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scisignal.aaf1371
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Funding
- General Research Fund of Hong Kong [HKU763811M]
- National Natural Science Foundation of China [31200883]
- Seed Funding for Basic Sciences of the University of Hong Kong [201101159010]
- NIH grant [MH059937]
- Undergraduate Research Fellowship Programme of the University of Hong Kong
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Some forms of familial Alzheimer's disease (FAD) are caused by mutations in presenilins (PSs), catalytic components of a gamma-secretase complex that cleaves target proteins, including amyloid precursor protein (APP). Calcium (Ca2+) dysregulation in cells with these FAD-causing PS mutants has been attributed to attenuated store-operated Ca2+ entry [SOCE; also called capacitative Ca2+ entry (CCE)]. CCE occurs when STIM1 detects decreases in Ca2+ in the endoplasmic reticulum (ER) and activates ORAI channels to replenish Ca2+ stores in the ER. We showed that CCE was attenuated by PS1-associated gamma-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 gamma-secretase cleavage of the STIM1 transmembrane domain at a sequence that was similar to the gamma-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 gamma-secretase inhibition or overexpression of STIM1. Our results indicate that gamma-secretase activity may physiologically regulate CCE by targeting STIM1 and that restoring STIM1 may be a therapeutic approach in AD.
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