Presenilin diversifies its portfolio

Presenilin, the catalytic member of the γ-secretase proteolytic complex, was discovered through its roles in generating Alzheimer's-disease-associated amyloid-β peptides from the amyloid-β precursor protein and in releasing the transcriptionally active domain of the receptor Notch. Recent work has revealed many additional cleavage substrates and interacting proteins, suggesting a diversity of roles for presenilin during development and adult life, some of which might contribute to Alzheimer's disease progression. Although many of these functions depend on the proteolytic activity of γ-secretase, others are independent of its role as a protease. Here, we review recent data on candidate functions for presenilin and its interactors and on their potential significance in disease.