A unifying model for functional difference and redundancy of presenilin-1 and -2 in cell apoptosis and differentiation.

Mutations in genes encoding the highly homologous proteins presenilin-1 and -2 (PS1 and PS2) are linked to the early onset of Alzheimer's disease (AD). Here, we report that polyclonal antibodies against Xenopus PSbeta (PS2), but not PSalpha (PS1), suppress the in vitro apoptotic activation of Xenopus egg extracts. To clarify the relationship between structural and functional differences in presenilins, we searched for presenilin homologues in various living sources, and found that presenilins were divided into three distinct groups, named alpha-, beta- and gamma-types, based on the size of the large hydrophilic loop (HL) regions as follows: HLalpha/HLbeta/HLgamma=4:3:6. No such size conservations were found in the N-terminal (NT) hydrophilic regions. Phylogenetic studies revealed that the presenilin genes were duplicated independently in different lineages of phyla/divisions, suggesting that there were functional requirements for and constraints on the generation and conservation of these HL sizes. On the basis of these findings, we propose a model postulating that both PS1 and PS2 can be differentiative or apoptotic when they are proteolytically processed within the HL regions or not, respectively, and PS1 may be more sensitive than PS2 to auto-proteolytic cleavage due to the larger size of the HL region of the former. Furthermore, the model assumes that C-terminal fragments (CTF) stabilized by phosphorylation may inhibit both the activities due to the dominant-negative effect. The model explains not only the functional redundancy but also apparently conflicting observations reported so far for PS1 and PS2.