کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
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1929323 | 1050452 | 2012 | 6 صفحه PDF | دانلود رایگان |

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.
Erlin-2 and γ-secretase interact (red dots) in BD3 cells.Figure optionsDownload as PowerPoint slideHighlights
► We find erlin-2 to be associated with active γ-secretase in brain tissue.
► We visualize this interaction in cells by using a proximity ligation assay.
► Silencing of erlin-2 expression results in reduced Aβ, but not NICD, levels.
► Modulating this interaction may be a strategy for treatment of Alzheimer disease.
Journal: Biochemical and Biophysical Research Communications - Volume 424, Issue 3, 3 August 2012, Pages 476–481