Assessment of normal and mutant human presenilin function in Caenorhabditis elegans.
We provide evidence that normal human presenilins can substitute for Caenorhabditis elegans SEL-12 protein in functional assays in vivo. In addition, six familial Alzheimer disease-linked mutant human presenilins were tested and found to have reduced ability to rescue the sel-12 mutant phenotype, suggesting that they have lower than normal presenilin activity. A human presenilin 1 deletion variant that fails to be proteolytically processed and a mutant SEL-12 protein that lacks the C terminus display considerable activity in this assay, suggesting that neither presenilin proteolysis nor the C terminus is absolutely required for normal presenilin function. We also show that sel-12 is expressed in most neural and nonneural cell types in all developmental stages. The reduced activity of mutant presenilins and as yet unknown gain-of-function properties may be a contributing factor in the development of Alzheimer disease.
Levitan
D
D
Howard Hughes Medical Institute, College of Physicans and Surgeons, Columbia University, New York, NY 10032, USA.
Doyle
T G
TG
Brousseau
D
D
Lee
M K
MK
Thinakaran
G
G
Slunt
H H
HH
Sisodia
S S
SS
Greenwald
I
I
D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics*; D029742:Caenorhabditis elegans Proteins; D017353:Gene Deletion; D018014:Gene Transfer Techniques; D015801:Helminth Proteins / Q000235:genetics*; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D053764:Presenilin-1; D053766:Presenilin-2; D017421:Sequence Analysis
D029742:Caenorhabditis elegans Proteins; D015801:Helminth Proteins; D008565:Membrane Proteins; C508853:PSEN1 protein, human; C508861:PSEN2 protein, human; D053764:Presenilin-1; D053766:Presenilin-2; C095907:SEL-12 protein, C elegans