Suppressor mutations for presenilin 1 familial Alzheimer disease mutants modulate γ-secretase activities

Eugene Futai, Satoko Osawa, Tetsuo Cai, Tomoya Fujisawa, Shoichi Ishiura, Taisuke Tomita

    研究成果: Article査読

    15 被引用数 (Scopus)

    抄録

    γ-Secretase is a multisubunit membrane protein complex containing presenilin (PS1) as a catalytic subunit. Familial Alzheimer disease (FAD) mutations within PS1 were analyzed in yeast cells artificially expressing membrane-bound substrate, amyloid precursor protein, or Notch fused to Gal4 transcriptional activator. The FAD mutations, L166P and G384A (Leu- 166 to Pro and Gly-384 to Ala substitution, respectively), were loss-of-function in yeast. We identified five amino acid substitutions that suppress the FAD mutations. The cleavage of amyloid precursor protein or Notch was recovered by the secondary mutations. We also found that secondary mutations alone activated the γ-secretase activity. FAD mutants with suppressor mutations, L432M or S438P within TMD9 together with a missense mutation in the second or sixth loops, regained γ-secretase activity when introduced into presenilin null mouse fibroblasts. Notably, the cells with suppressor mutants produced a decreased amount of Aβ42, which is responsible for Alzheimer disease. These results indicate that the yeast system is useful to screen for mutations and chemicals that modulate γ-secretase activity.

    本文言語English
    ページ(範囲)435-446
    ページ数12
    ジャーナルJournal of Biological Chemistry
    291
    1
    DOI
    出版ステータスPublished - 2016 1月 1

    ASJC Scopus subject areas

    • 生化学
    • 分子生物学
    • 細胞生物学

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