ENDOPROTEOLYTIC CLEAVAGE AND PROTEASOMAL DEGRADATION OF PRESENILIN-2 IN TRANSFECTED CELLS

Mutations in the presenilin genes, PS1 and PS2, cause a major portion of early onset familial Alzheimer's disease (FAD), The biological role s of the presenilins and how their pathological mutations confer FAD a re unknown, In this study, we set out to examine the processing and de gradation pathways of PS2. For regulated expression of PS2, we have es tablished inducible cell lines expressing PS2 under the tight control of the tetracycline-responsive transactivator. Western blot analysis r evealed that PS2 was detected as an similar to 53-55-kDa polypeptide ( 54-kDa PS2) as well as a high molecular mass form (HMW-PS2). Using a s tably transfected, inducible cell system, we have found that PS2 is pr oteolytically cleaved into two stable cellular polypeptides including an similar to 20-kDa C-terminal fragment and an similar to 34-kDa N-te rminal fragment. PS2 is polyubiquitinated in vivo, and the degradation of PS2 is inhibited by proteasome inhibitors, N-acetyl-L-leucinal-L-n orleucinal and lactacystin. Our studies suggest that PS2 normally unde rgoes endoproteolytic cleavage and is degraded via the proteasome path way.