Presenilin Proteins
61
4.5 Presenilins Are Required for Notch Signaling
PS proteins facilitate Notch signaling. This is supported by the finding
that a defect in the PS homologue of Caenorhabditis elegans results in a
Notch phenotype, which can be fully rescued by transgenic expression
of human PS 1 and PS2 (Baumeister et al. 1997; Levitan et al. 1996).
Furthermore, a deletion of the PS 1 gene in mice results in abnormal
embryonic development causing a fatal phenotype, which is highly
similar to that caused by the deletion of the Notch gene (Shen et al.
1997; Wong et al. 1997). Moreover, it has been recently demonstrated
that cells derived from PS-I- mice fail to undergo the critical intramembranous cleavage of Notch (De Strooper et al. 1999; Fig. 1). This cleavage is required for the release of the Notch intracellular domain (NICD),
which is then transported to the nucleus where it regulates gene transcription (Struh1 and Adachi 1998; Schroeter et al. 1998). Interestingly,
the dominant negative aspartate mutations described above also abolish
the proteolytic release of NICD and the mutant cDNAs did not rescue
the Notch phenotype in C. elegans with a defective endogenous PS gene
(Steiner and Haass, submitted).
4.6 Presenilins: Targets for Anti-Alzheimer's Drugs?
Based on the results described above, it appears that PS proteins are
involved in the intramembranous cleavage of a variety of membrane
proteins such as ~APP, Notch, and APLP (which is a ~APP homologous
protein), and it is very tempting to speculate that PS proteins are identical with the y-secretase. Although this model is quite convincing, there
are still many open questions, which may imply that PS molecules are
involved in targeting selected membrane proteins to the cell surface
(Naruse et al. 1998) and therefore affect ~APP and Notch processing
rather indirectly. If indeed the PS proteins are identical with the y-secretase, inhibition of PS function may be a major target for Amyloid-lowering drugs. However, due to the essential function of PS proteins in
Notch signaling, inhibition of their biological activity may cause fatal
side effects.
61
4.5 Presenilins Are Required for Notch Signaling
PS proteins facilitate Notch signaling. This is supported by the finding
that a defect in the PS homologue of Caenorhabditis elegans results in a
Notch phenotype, which can be fully rescued by transgenic expression
of human PS 1 and PS2 (Baumeister et al. 1997; Levitan et al. 1996).
Furthermore, a deletion of the PS 1 gene in mice results in abnormal
embryonic development causing a fatal phenotype, which is highly
similar to that caused by the deletion of the Notch gene (Shen et al.
1997; Wong et al. 1997). Moreover, it has been recently demonstrated
that cells derived from PS-I- mice fail to undergo the critical intramembranous cleavage of Notch (De Strooper et al. 1999; Fig. 1). This cleavage is required for the release of the Notch intracellular domain (NICD),
which is then transported to the nucleus where it regulates gene transcription (Struh1 and Adachi 1998; Schroeter et al. 1998). Interestingly,
the dominant negative aspartate mutations described above also abolish
the proteolytic release of NICD and the mutant cDNAs did not rescue
the Notch phenotype in C. elegans with a defective endogenous PS gene
(Steiner and Haass, submitted).
4.6 Presenilins: Targets for Anti-Alzheimer's Drugs?
Based on the results described above, it appears that PS proteins are
involved in the intramembranous cleavage of a variety of membrane
proteins such as ~APP, Notch, and APLP (which is a ~APP homologous
protein), and it is very tempting to speculate that PS proteins are identical with the y-secretase. Although this model is quite convincing, there
are still many open questions, which may imply that PS molecules are
involved in targeting selected membrane proteins to the cell surface
(Naruse et al. 1998) and therefore affect ~APP and Notch processing
rather indirectly. If indeed the PS proteins are identical with the y-secretase, inhibition of PS function may be a major target for Amyloid-lowering drugs. However, due to the essential function of PS proteins in
Notch signaling, inhibition of their biological activity may cause fatal
side effects.