The presenilin-1 ΔE9 mutation results in reduced γ-secretase activity, but not total loss of PS1 function, in isogenic human stem cells

Cell Rep. 2013 Nov 27;5(4):974-85. doi: 10.1016/j.celrep.2013.10.018. Epub 2013 Nov 14.


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 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / genetics
  • Amyloid Precursor Protein Secretases / antagonists & inhibitors
  • Amyloid Precursor Protein Secretases / genetics*
  • Amyloid Precursor Protein Secretases / metabolism
  • Amyloid beta-Peptides / biosynthesis
  • Amyloid beta-Peptides / genetics
  • Amyloid beta-Protein Precursor / metabolism
  • Base Sequence
  • Cell Line
  • Cells, Cultured
  • Green Fluorescent Proteins / genetics
  • Humans
  • Mutation
  • Neurogenesis / genetics*
  • Neurons / cytology
  • Peptide Fragments / biosynthesis
  • Peptide Fragments / genetics
  • Pluripotent Stem Cells / cytology
  • Pluripotent Stem Cells / enzymology*
  • Presenilin-1 / genetics*
  • Protein Processing, Post-Translational
  • Sequence Analysis, DNA


  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • PSEN1 protein, human
  • Peptide Fragments
  • Presenilin-1
  • amyloid beta-protein (1-40)
  • amyloid beta-protein (1-42)
  • Green Fluorescent Proteins
  • Amyloid Precursor Protein Secretases