Abstract
Mutations in presenilins result in familial Alzheimer's disease (FAD). Presenilins encode a catalytic subunit of the γ-secretase complex, and FAD mutations in presenilins alter γ-secretase activity. Many FAD mutations in presenilins also affect intracellular calcium signaling. To explain these results, it was proposed that presenilins also function as endoplasmic reticulum (ER) calcium leak channels and that this function is disrupted by FAD mutations. Although this hypothesis has been controversial, new research supports the calcium leak channel hypothesis. One group reported the presence of putative ion-conduction pore in the high-resolution crystal structure of bacterial presenilin homolog PSH1. Another group identified an essential role for presenilins in mediating ER calcium leak in a cell-based screen for calcium homeostasis modulators. These results should enable the field to move forward and to focus on exploring connections between FAD mutations in presenilins, changes in γ-secretase and ER Ca(2+) leak functions, and development of the disease.