Functional cloning of genes involved in T-cell receptor-induced programmed cell death.

Programmed cell death (PCD) is a normal event under genetic control that regulates the life span of different cell types in multicellular organisms. Among other physiological processes, PCD plays a pivotal role in the regulation of the immune system. Using a functional selection strategy we have isolated and characterized genes involved in T-cell receptor-induced apoptosis. One, ALG-2, is a Ca(2+)-binding protein that participates in regulatory events that occur late in the apoptotic program, where several death signals converge. Another, ALG-3, is a mouse homologue of the chromosome 1 familial Alzheimer's disease gene PS2. ALG-3 codes for a truncated PS2 polypeptide that antagonizes the apoptotic role of PS2. A PS2 mutation associated with Alzheimer's disease generates a molecule with enhanced apoptotic activity indicating that it might accelerate the process of neurodegeneration that occurs in this disease.