Erlin-2 is associated with active γ-secretase in brain and affects amyloid β-peptide production

Biochem Biophys Res Commun. 2012 Aug 3;424(3):476-81. doi: 10.1016/j.bbrc.2012.06.137. Epub 2012 Jul 4.

Abstract

The transmembrane protease complex γ-secretase is responsible for the generation of the neurotoxic amyloid β-peptide (Aβ) from its precursor (APP). Aβ has a causative role in Alzheimer disease, and thus, γ-secretase is a therapeutic target. However, since there are more than 70 γ-secretase substrates besides APP, selective inhibition of APP processing is required. Recent data indicates the existence of several γ-secretase associated proteins (GSAPs) that affect the selection and processing of substrates. Here, we use a γ-secretase inhibitor for affinity purification of γ-secretase and associated proteins from microsomes and detergent resistant membranes (DRMs) prepared from rat or human brain. By tandem mass spectrometry we identified a novel brain GSAP; erlin-2. This protein was recently reported to reside in DRMs in the ER. A proximity ligation assay, as well as co-immunoprecipitation, confirmed the association of erlin-2 with γ-secretase. We found that a higher proportion of erlin-2 was associated with γ-secretase in DRMs than in soluble membranes. siRNA experiments indicated that reduced levels of erlin-2 resulted in a decreased Aβ production, whereas the effect on Notch processing was limited. In summary, we have found a novel brain GSAP, erlin-2, that resides in DRMs and affects Aβ production.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / metabolism
  • Amyloid Precursor Protein Secretases / metabolism*
  • Amyloid beta-Peptides / biosynthesis*
  • Animals
  • Brain / metabolism*
  • Humans
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • RNA, Small Interfering / genetics
  • Rats
  • Rats, Sprague-Dawley

Substances

  • Amyloid beta-Peptides
  • ERLIN2 protein, human
  • Erlin2 protein, rat
  • Membrane Proteins
  • RNA, Small Interfering
  • Amyloid Precursor Protein Secretases