The Presenilin-1 ΔE9 mutation results in reducedγ-secretase activity but not total loss of PS1 function in isogenichuman stem cells

摘要

Presenilin 1 (PS1) is the catalytic core of γ-secretase, which cleaves type-1 transmembrane proteins including the amyloid precursor protein (APP). PS1 also has γ-secretase independent functions and dominant PS1 missense mutations are the most common cause of familial Alzheimer’s disease (FAD). Whether PS1 FAD mutations are gain or loss-of-function remains controversial, primarily because most studies have relied on overexpression in mouse and/or non-neuronal systems. We used isogenic euploid human iPSC lines to generate and study an allelic series of PS1 mutations including heterozygous null mutations and homozygous and heterozygous FAD PS1 mutations. Rigorous analysis of this allelic series in differentiated, purified neurons allowed us to resolve this controversy and to conclude that FAD PS1 mutations, expressed at normal levels in the appropriate cell-type, impair γ-secretase activity, but do not disrupt γ-secretase independent functions of PS1. Thus, FAD PS1 mutations do not act as simple loss of PS1 function, but instead dominantly gain an activity toxic to some, but not all PS1 functions.