Role of X11 and ubiquilin as In Vivo Regulators of the Amyloid Precursor Protein in DrosophilaReport as inadecuate

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The Amyloid Precursor Protein APP undergoes sequential proteolytic cleavages through the action of β- and γ-secretase, which result in the generation of toxic β-amyloid Aβ 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 γ-secretase is likely to provide insight into AD pathogenesis. Here, using transgenic flies that act as reporters for endogenous γ-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 γ-secretase cleavage of APP or Notch, another γ-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 Aβ production and-or secretion in APP transgenic mice, but does not act on γ-secretase directly, X11 may represent an attractive therapeutic target for AD.

Author: Garrett G. Gross, R. M. Renny Feldman , Atish Ganguly , Jinhui Wang, Hong Yu, Ming Guo



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