title: Erlin-2 is associated with active γ-secretase in brain and affects amyloid β-peptide production.
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.
authors: Karolinska Institutet Dainippon Sumitomo Pharma Alzheimer Center, KI-Alzheimer Disease Research Center, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Novum, Stockholm SE-141 86, Sweden.
authors: Yasuhiro
authors: Y
authors: Teranishi
authors: Ji-Yeun
authors: JY
authors: Hur
authors: Gucci Jijuan
authors: GJ
authors: Gu
authors: Takahiro
authors: T
authors: Kihara
authors: Taizo
authors: T
authors: Ishikawa
authors: Takeshi
authors: T
authors: Nishimura
authors: Bengt
authors: B
authors: Winblad
authors: Homira
authors: H
authors: Behbahani
authors: Masood
authors: M
authors: Kamali-Moghaddam
authors: Susanne
authors: S
authors: Frykman
authors: Lars O
authors: LO
authors: Tjernberg
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000096:biosynthesis*; D000818:Animals; D001921:Brain / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D016229:Amyloid beta-Peptides; C121703:ERLIN2 protein, human; C576271:Erlin2 protein, rat; D008565:Membrane Proteins; D034741:RNA, Small Interfering; D053829:Amyloid Precursor Protein Secretases