First Author | Teranishi Y | Year | 2012 |
Journal | Biochem Biophys Res Commun | Volume | 424 |
Issue | 3 | Pages | 476-81 |
PubMed ID | 22771797 | Mgi Jnum | J:201292 |
Mgi Id | MGI:5512937 | Doi | 10.1016/j.bbrc.2012.06.137 |
Citation | Teranishi Y, et al. (2012) Erlin-2 is associated with active gamma-secretase in brain and affects amyloid beta-peptide production. Biochem Biophys Res Commun 424(3):476-81 |
abstractText | The transmembrane protease complex gamma-secretase is responsible for the generation of the neurotoxic amyloid beta-peptide (Abeta) from its precursor (APP). Abeta has a causative role in Alzheimer disease, and thus, gamma-secretase is a therapeutic target. However, since there are more than 70 gamma-secretase substrates besides APP, selective inhibition of APP processing is required. Recent data indicates the existence of several gamma-secretase associated proteins (GSAPs) that affect the selection and processing of substrates. Here, we use a gamma-secretase inhibitor for affinity purification of gamma-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 gamma-secretase. We found that a higher proportion of erlin-2 was associated with gamma-secretase in DRMs than in soluble membranes. siRNA experiments indicated that reduced levels of erlin-2 resulted in a decreased Abeta 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 Abeta production. |