Nishimura M, Yu G, Levesque G, Zhang D M, Ruel L, Chen F, Milman P, Holmes E, Liang Y, Kawarai T, Jo E, Supala A, Rogaeva E, Xu D M, Janus C, Levesque L, Bi Q, Duthie M, Rozmahel R, Mattila K, Lannfelt L, Westaway D, Mount H T, Woodgett J, St George-Hyslop P
Centre for Research in Neurodegenerative Diseases, Department of Medicine (Neurology), University of Toronto, Ontario, Canada.
Nat Med. 1999 Feb;5(2):164-9. doi: 10.1038/5526.
The presenilin proteins are components of high-molecular-weight protein complexes in the endoplasmic reticulum and Golgi apparatus that also contain beta-catenin. We report here that presenilin mutations associated with familial Alzheimer disease (but not the non-pathogenic Glu318Gly polymorphism) alter the intracellular trafficking of beta-catenin after activation of the Wnt/beta-catenin signal transduction pathway. As with their effect on betaAPP processing, the effect of PS1 mutations on trafficking of beta-catenin arises from a dominant 'gain of aberrant function' activity. These results indicate that mistrafficking of selected presenilin ligands is a candidate mechanism for the genesis of Alzheimer disease associated with presenilin mutations, and that dysfunction in the presenilin-beta-catenin protein complexes is central to this process.
早老素蛋白是内质网和高尔基体中高分子量蛋白复合物的组成部分，这些复合物中还含有β-连环蛋白。我们在此报告，与家族性阿尔茨海默病相关的早老素突变（而非非致病性的Glu318Gly多态性）在Wnt/β-连环蛋白信号转导通路激活后会改变β-连环蛋白的细胞内运输。与它们对β淀粉样前体蛋白（βAPP）加工的影响一样，早老素1（PS1）突变对β-连环蛋白运输的影响源于一种显性的“异常功能获得”活性。这些结果表明，特定早老素配体的运输错误是与早老素突变相关的阿尔茨海默病发生的一种候选机制，并且早老素-β-连环蛋白蛋白复合物的功能障碍是这一过程的核心。
