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

• DOI: 10.1016/j.bbrc.2012.06.137
• Publication Date: 2012-07-05T04:25:54Z
• Authors: Yasuhiro Teranishi; Ji-Yeun Hur; Gucci Jijuan Gu; Takahiro Kihara; Taizo Ishikawa; Takeshi Nishimura; Bengt Winblad; Homira Behbahani; Masood Kamali-Mog...; Susanne Frykman; Lars O. Tjernberg
• Keywords: 0301 basic medicine; Amyloid beta-Peptides; Brain; Membrane Proteins; Rats; 3. Good health; Rats, Sprague-Dawley; Mice; 03 medical and health sciences; Alzheimer Disease; Animals; Humans; Amyloid Precursor Protein Secretases; RNA, Small Interfering

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.