title: Assessment of normal and mutant human presenilin function in Caenorhabditis elegans.
abstract: 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.
authors.affiliation: Howard Hughes Medical Institute, College of Physicans and Surgeons, Columbia University, New York, NY 10032, USA.
authors.forename: D
authors.initials: D
authors.lastname: Levitan
authors.forename: T G
authors.initials: TG
authors.lastname: Doyle
authors.forename: D
authors.initials: D
authors.lastname: Brousseau
authors.forename: M K
authors.initials: MK
authors.lastname: Lee
authors.forename: G
authors.initials: G
authors.lastname: Thinakaran
authors.forename: H H
authors.initials: HH
authors.lastname: Slunt
authors.forename: S S
authors.initials: SS
authors.lastname: Sisodia
authors.forename: I
authors.initials: I
authors.lastname: Greenwald
mesh_terms: 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
chemical_list: 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