Presenilin diversifies its portfolio

Presenilin, the catalytic member of the gamma-secretase proteolytic complex, was discovered through its roles in generating Alzheimer's-disease-associated amyloid-P peptides from the amyloid-beta 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 gamma-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.