Approximately 50% of familial Alzheimer's disease (FAD) results from a mutation in one of two genes, PS1 or PS2 (1,2), that encode closely related proteins now named presenilins. Heterozygosity for presenilin mutations is correlated with increased levels of a form of amyloid beta-peptide, Ab1-42(43), that is particularly prone to aggregation and deposition in the brain (3). Neither the mechanism underlying this increase in amyloid peptide levels nor the wild-type function of the presenilins has been elucidated. Two C. elegans presenilin homologs,
spe-4 and
sel-12, were identified initially in genetic screens (4,5).
spe-4 animals make defective sperm whereas
sel-12 animals are egg-laying defective (Egl). Levitan et al. (6) have shown that the Egl phenotype of
sel-12 animals can be rescued by expression of the human PS1 or PS2 genes. Expression of the PS1 gene containing FAD-associated mutations rescues the
sel-12 Egl defect less well than does expression of the wild-type PS1 gene, suggesting that these mutations impair presenilin activity (6) and may cause FAD by compromising presenilin function. A potential third C. elegans presenilin gene was recently identified as a predicted ORF in the sequence of the cosmid C18E3 reported by the Sequencing Consortium. This ORF, provisionally named C18E3.PSL, shares 35-40% amino acid identity with other presenilins. As a first step toward determining the function of C18E3.PSL, we attempted to identify mutations in this ORF using a strategy in which worms were mutagenized with several different types of mutagens and then PCR was used to screen for deletions. Using a combination of UV light and trimethylpsoralen (7), we identified a 1.2 kb deletion that begins about 450 bp upstream of the predicted C18E3.PSL initiation codon and ends in the third predicted intron. We are currently analyzing the phenotype of the deletion mutant. (1) Sherrington et al. (1995) Nature 375:754; (2) Levy-Lehad et al. (1995) Science 269:973; (3) Selkoe (1997) Science 275:630; (4) L'Hernault and Arduengo (1992) J. Cell. Biol. 119:55; (5) Levitan and Greenwald (1995) Nature 377: 351; (6) Levitan et al. (1996). PNAS 93:14940; (7) Yandell et al. (1994) PNAS 91:1381.