Presenilins form ER Ca2+ leak channels, a function disrupted by familial Alzheimer's disease-linked mutations
- 1Department of Physiology, UT Southwestern Medical Center at Dallas, Dallas, TX 75390, USA.
- 0Department of Physiology, UT Southwestern Medical Center at Dallas, Dallas, TX 75390, USA.
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View abstract on PubMed
Summary
This summary is machine-generated.Presenilins form ion channels, regulating calcium (Ca2+) signaling crucial for brain health. Familial Alzheimer's disease mutations disrupt this function, supporting the Ca2+ hypothesis of Alzheimer's disease.
Area Of Science
- Neuroscience
- Molecular Biology
- Genetics
Background
- Alzheimer's disease (AD) is a neurodegenerative disorder.
- Presenilin (PS) mutations cause familial AD (FAD) and are linked to calcium (Ca2+) signaling defects.
Purpose Of The Study
- Investigate the role of presenilins in Ca2+ signaling.
- Determine if FAD mutations affect presenilin ion channel function.
Main Methods
- Planar lipid bilayer experiments to assess ion channel activity.
- Experiments with PS1/2 double knockout (DKO) mouse embryonic fibroblasts (MEFs).
- Rescue experiments expressing wild-type and mutant presenilins in DKO MEFs.
Main Results
- Wild-type presenilins form Ca2+-permeable ion channels; FAD mutants do not.
- Presenilins account for ~80% of endoplasmic reticulum Ca2+ leak.
- Ca2+ leak function is independent of gamma-secretase activity.
- Wild-type presenilins rescue Ca2+ signaling in DKO MEFs, but mutants do not.
Conclusions
- Presenilins possess a Ca2+ leak function independent of gamma-secretase activity.
- FAD mutations in presenilins impair Ca2+ signaling.
- Findings support the Ca2+ hypothesis of Alzheimer's disease.
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