Figure 1.

Rescue of the sel-12 Egl and abnormal vulva phenotypes by normal and mutant human presenilins. The data are shown for transgenic lines generated by injecting the construct being tested at a concentration of 20 μg/ml. Each line in the histogram represents data for an independent transgenic line; the number of hermaphrodites scored is shown above each line. The transgene is indicated on the horizontal axis. The percentage of Egl⁺ hermaphrodites is indicated on the vertical axis. Egl⁺ signifies robust egg-laying after 2 days; this criterion is very stringent and underestimates the degree of rescuing activity. The ability of PS1 point mutant proteins (data not shown) and the PS1ΔE9 mutant protein (see Fig. 2) to rescue sel-12(ar131) was further reduced when transgenic lines were generated by injecting DNA at a concentration of 2 μg/ml. Most PS1 mutations that cause Alzheimer disease affect amino acids that are identical in SEL-12. The N termini of PS1, PS2, and SEL-12 are not well conserved and are of different lengths. Therefore, for the mutations used herein, the amino acid corresponding to Met-146 in PS1 is Met-115 in SEL-12; PS1 His-163 is SEL-12 His-132; PS1 Ala-246 is SEL-12 Val-216; PS1 Leu-286 is SEL-12 Leu-255; PS1 Cys-410 is SEL-12 Cys-384. The ΔE9 mutation inhibits cleavage of PS1 (17); we note that SEL-12 is cleaved in a comparable position (24). Note that the sel-12 cDNA used (11) has a frameshift mutation, beginning at codon 413, resulting in the substitution of 31 amino acids C-terminal to the frameshift mutation by 49 amino acids.