| First Author | Cheung KH | Year | 2010 |
| Journal | Sci Signal | Volume | 3 |
| Issue | 114 | Pages | ra22 |
| PubMed ID | 20332427 | Mgi Jnum | J:185414 |
| Mgi Id | MGI:5428409 | Doi | 10.1126/scisignal.2000818 |
| Citation | Cheung KH, et al. (2010) Gain-of-function enhancement of IP3 receptor modal gating by familial Alzheimer's disease-linked presenilin mutants in human cells and mouse neurons. Sci Signal 3(114):ra22 |
| abstractText | Familial Alzheimer's disease (FAD) is caused by mutations in amyloid precursor protein or presenilins (PS1 and PS2). Many FAD-linked PS mutations affect intracellular calcium (Ca(2+)) homeostasis by mechanisms proximal to and independent of amyloid production, although the molecular details are controversial. We found that several FAD-causing PS mutants enhance gating of the inositol trisphosphate receptor (IP(3)R) Ca(2+) release channel by a gain-of-function effect that mirrored the genetics of FAD and was independent of secretase activity. In contrast, wild-type PS or PS mutants that cause frontotemporal dementia had no such effect. FAD-causing PS mutants altered the modes in which the IP(3)R channel gated. Recordings of endogenous IP(3)R in lymphoblasts derived from individuals with FAD or cortical neurons of asymptomatic PS1-AD mice revealed that they were more likely than IP(3)R in cells with wild-type PS to dwell in a high open-probability burst mode, resulting in enhanced Ca(2+) signaling. These results indicate that exaggerated Ca(2+) signaling through IP(3)R-PS interaction is a disease-specific and robust proximal mechanism in FAD. |
