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 overexpressionin mouse and/or nonneuronal systems. We used isogenic euploid human induced pluripotent stem cell 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
Bibliographical noteFunding Information:
The authors are funded by the California Institute of Regenerative Medicine (RT2-01927 awarded to L.S.B.G. and RB3-05083 awarded to K.Z.) and the National Institutes of Health/National Institutes of Aging (R01AG032180). J.E.Y. is supported by the A.P. Giannini Foundation for Medical Research. G.W. is supported by an institutional training grant (2T32AG000216-21). The authors thank Angels Almenar-Queralt for insightful discussion and feedback, Lauren Fong for helpful input, and Dr. Toni Cathomen (University Medical Center Freiburg) and Christien Bednarski for kindly providing protocols and plasmids for performing the episomal assay.