Assessment of normal and mutant human presenilin function in Caenorhabditis elegans

Assessment of normal and mutant human presenilin function in Caenorhabditis elegans

^*Howard Hughes Medical Institute, ^†Department of Biochemistry and Molecular Biophysics, and ^‡Integrated Program in Biochemistry and Molecular Biophysics, College of Physicans and Surgeons, Columbia University, New York, NY 10032; and Departments of ^§Pathology and ^¶Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD 21205

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.

Footnotes

↵ ‖ To whom reprint requests should be addressed at: Howard Hughes Medical Institute and Department of Biochemistry and Molecular Biophysics, 701 West 168th Street, Room 720A, College of Physicians and Surgeons, Columbia University, New York, NY 10032. e-mail: greenwald{at}cuccfa.ccc.columbia.edu.
Thomas W. Cline, University of California, Berkeley, CA
Abbreviation: Egl, egg-laying defective.