Dominant negative effect of the loss-of-function γ-secretase mutants on the wild-type enzyme through heterooligomerization

Proc Natl Acad Sci U S A. 2017 Nov 28;114(48):12731-12736. doi: 10.1073/pnas.1713605114. Epub 2017 Oct 9.

Abstract

γ-secretase is an intramembrane protease complex consisting of nicastrin, presenilin-1/2, APH-1a/b, and Pen-2. Hydrolysis of the 99-residue transmembrane fragment of amyloid precursor protein (APP-C99) by γ-secretase produces β-amyloid (Aβ) peptides. Pathogenic mutations in PSEN1 and PSEN2, which encode the catalytic subunit presenilin-1/2 of γ-secretase, lead to familial Alzheimer's disease in an autosomal dominant manner. However, the underlying mechanism of how the mutant PSEN gene may affect the function of the WT allele remains to be elucidated. Here we report that each of the loss-of-function γ-secretase variants that carries a PSEN1 mutation suppresses the protease activity of the WT γ-secretase on Aβ production. Each of these γ-secretase variants forms a stable oligomer with the WT γ-secretase in vitro in the presence of the detergent CHAPSO {3-[(3-cholamidopropyl)dimethylammonio]-2-hydroxy-1-propanesulfonate}, but not digitonin. Importantly, robust protease activity of γ-secretase is detectable in the presence of CHAPSO, but not digitonin. These experimental observations suggest a dominant negative effect of the γ-secretase, in which the protease activity of WT γ-secretase is suppressed by the loss-of-function γ-secretase variants through hetero-oligomerization. The relevance of this finding to the genesis of Alzheimer's disease is critically evaluated.

Keywords: Alzheimer’s disease; dominant negative effect; oligomerization; presenilin 1; γ-secretase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / genetics
  • Alzheimer Disease / metabolism
  • Alzheimer Disease / pathology
  • Amyloid Precursor Protein Secretases / chemistry
  • Amyloid Precursor Protein Secretases / genetics*
  • Amyloid Precursor Protein Secretases / metabolism
  • Amyloid beta-Peptides / genetics*
  • Amyloid beta-Peptides / metabolism
  • Cholic Acids / chemistry
  • Cloning, Molecular
  • Detergents / chemistry
  • Digitonin / chemistry
  • Endopeptidases
  • Gene Expression
  • HeLa Cells
  • Humans
  • Membrane Proteins / chemistry
  • Membrane Proteins / genetics*
  • Membrane Proteins / metabolism
  • Models, Biological
  • Mutation
  • Peptide Fragments / genetics*
  • Peptide Fragments / metabolism
  • Peptide Hydrolases / chemistry
  • Peptide Hydrolases / genetics
  • Peptide Hydrolases / metabolism
  • Presenilin-1 / chemistry
  • Presenilin-1 / genetics*
  • Presenilin-1 / metabolism
  • Presenilin-2 / chemistry
  • Presenilin-2 / genetics*
  • Presenilin-2 / metabolism
  • Protein Multimerization
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism

Substances

  • Amyloid beta-Peptides
  • Cholic Acids
  • Detergents
  • Membrane Proteins
  • PSEN1 protein, human
  • PSENEN protein, human
  • Peptide Fragments
  • Presenilin-1
  • Presenilin-2
  • Recombinant Proteins
  • amyloid beta-protein (1-40)
  • amyloid beta-protein (1-42)
  • chapso
  • APH1A protein, human
  • APH1B protein, human
  • Amyloid Precursor Protein Secretases
  • Endopeptidases
  • Peptide Hydrolases
  • Digitonin