Calsenilin: A calcium-binding protein that interacts with the presenilins and regulates the levels of a presenilin fragment

Most early-onset familiar Alzheimer disease (AD) cases are caused by mutations ill the highly related genes presenilin 1 (PS1) and presenilin 2 (PS2)(1-3). Presenilin mutations produce increases in beta-amyloid (A beta) formation and apoptosis in many experimental systems. A cDNA (ALG-3) encoding the last 103 amino acids of PS2 has been identified as a potent inhibitor of apoptosis(4,5). Using this PS2 domain in the yeast two-hybrid system, we have identified a neuronal protein that binds calcium and presenilin, which we call calsenilin. Calsenilin interacts with both PS1 and PS2 in cultured cells, and can regulate the levels of a proteolytic product of PS2. Thus, calsenilin may mediate the effects of wild-type and mutant presenilins on apoptosis and on A beta formation. Further characterization of calsenilin may lead to an understanding of the normal role of the presenilins and of the role of the presenilins in Alzheimer disease.