Levitan D, Doyle T G, Brousseau D, Lee M K, Thinakaran G, Slunt H H, Sisodia S S, Greenwald I
Howard Hughes Medical Institute, College of Physicans and Surgeons, Columbia University, New York, NY 10032, USA.
Proc Natl Acad Sci U S A. 1996 Dec 10;93(25):14940-4. doi: 10.1073/pnas.93.25.14940.
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.
我们提供的证据表明，在体内功能测定中，正常的人类早老素可以替代秀丽隐杆线虫的SEL-12蛋白。此外，对六种与家族性阿尔茨海默病相关的突变型人类早老素进行了测试，发现它们挽救sel-12突变体表型的能力降低，这表明它们的早老素活性低于正常水平。一种无法进行蛋白水解加工的人类早老素1缺失变体和一种缺乏C末端的突变型SEL-12蛋白在此测定中显示出相当的活性，这表明早老素的蛋白水解作用和C末端对于正常的早老素功能都不是绝对必需的。我们还表明，sel-12在所有发育阶段的大多数神经和非神经细胞类型中都有表达。突变型早老素活性的降低以及尚未明确的功能获得特性可能是阿尔茨海默病发展的一个促成因素。
