Ballads of a protein quartet

摘要

The fate of neurons in the developing brain and in Alzheimer's disease may lie with a four-protein complex that regulates the cleavage of two molecules spanning the cell membrane. The role of each protein is now being unveiled. Scientific discoveries often originate in surprising places. Some years ago, for instance, researchers looking at how the brain develops received help from an unexpected quarter: studies of patients with Alzheimer's disease. This disease is characterized in part by the abnormal accumulation, in the brain, of a protein called amyloid β-peptide (Aβ), which is a fragment of a larger protein, the amyloid precursor protein (APP), that sits across the outer membrane of nerve cells. Two enzymatic activities are involved in precisely snipping APP to produce Aβ, which is then shed into the brain. Curiously, one of these activities―dubbed γ-secretase―was later discovered also to cleave Notch, a receptor protein that lies on the cell surface, and thereby to affect the way in which Notch regulates gene expression during normal development. On page 438 of this issue, Takasugi and colleagues add to our understanding of how APP and Notch are processed. Using genes and cells from flies and humans, and the powerful new technology of RNA interference, these authors establish specific roles for four different proteins underlying γ-secretase activity.