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• W2146142927 endingPage "e2495" @default.
• W2146142927 startingPage "e2495" @default.
• W2146142927 abstract "The Amyloid Precursor Protein (APP) undergoes sequential proteolytic cleavages through the action of beta- and gamma-secretase, which result in the generation of toxic beta-amyloid (Abeta) peptides and a C-terminal fragment consisting of the intracellular domain of APP (AICD). Mutations leading to increased APP levels or alterations in APP cleavage cause familial Alzheimer's disease (AD). Thus, identification of factors that regulate APP steady state levels and/or APP cleavage by gamma-secretase is likely to provide insight into AD pathogenesis. Here, using transgenic flies that act as reporters for endogenous gamma-secretase activity and/or APP levels (GAMAREP), and for the APP intracellular domain (AICDREP), we identified mutations in X11L and ubiquilin (ubqn) as genetic modifiers of APP. Human homologs of both X11L (X11/Mint) and Ubqn (UBQLN1) have been implicated in AD pathogenesis. In contrast to previous reports, we show that overexpression of X11L or human X11 does not alter gamma-secretase cleavage of APP or Notch, another gamma-secretase substrate. Instead, expression of either X11L or human X11 regulates APP at the level of the AICD, and this activity requires the phosphotyrosine binding (PTB) domain of X11. In contrast, Ubqn regulates the levels of APP: loss of ubqn function leads to a decrease in the steady state levels of APP, while increased ubqn expression results in an increase in APP levels. Ubqn physically binds to APP, an interaction that depends on its ubiquitin-associated (UBA) domain, suggesting that direct physical interactions may underlie Ubqn-dependent regulation of APP. Together, our studies identify X11L and Ubqn as in vivo regulators of APP. Since increased expression of X11 attenuates Abeta production and/or secretion in APP transgenic mice, but does not act on gamma-secretase directly, X11 may represent an attractive therapeutic target for AD." @default.
• W2146142927 created "2016-06-24" @default.
• W2146142927 creator A5010584775 @default.
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• W2146142927 creator A5075662890 @default.
• W2146142927 date "2008-06-25" @default.
• W2146142927 modified "2023-10-09" @default.
• W2146142927 title "Role of X11 and ubiquilin as In Vivo Regulators of the Amyloid Precursor Protein in Drosophila" @default.
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• W2146142927 doi "https://doi.org/10.1371/journal.pone.0002495" @default.
• W2146142927 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/2429963" @default.
• W2146142927 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/18575606" @default.
• W2146142927 hasPublicationYear "2008" @default.
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