The Presenilin-1 ΔE9 Mutation Results in Reduced γ-Secretase Activity, but Not Total Loss of PS1 Function, in Isogenic Human Stem Cells

• DOI: 10.1016/j.celrep.2013.10.018
• Publication Date: 2013-11-14T16:31:49Z
• Authors: Grace Woodruff; Jessica E. Young; Fernando J. Martinez; Floyd Buen; Athurva Gore; Jennifer Kinaga; Zhe Li; Shauna H. Yuan; Kun Zhang; Lawrence S.B. Gol...
• Keywords: Null allele; Loss function

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