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- W1988658526 abstract "Abeta generation is caused by sequential cleavage of the amyloid precursor protein (APP) by two proteases, beta-site of APP cleaving-enzyme (BACE) and Gamma-secretase. Complex transport including internalization and return to the surface is necessary for this process. GGA1, a transport adaptor of the Golgi-localized gamma-ear-containing ARF-binding (GGA) family, has been shown to interact with BACE via its VHS-domain. We analyzed the differential roles of GGA1, GGA2 and GGA3 upon co-localization and interaction with BACE and effects upon APP-processing. In addition we tested the hypothesis that serine-phosphorylation of GGA1 and GGA3 affects BACE-interaction. We applied confocal imaging and fluorescence lifetime imaging microscopy (FLIM) for colocalization and interaction studies, an electrochemiluminescence-based assay to measure the influence of all three GGA upon APP processing, westernblotting to measure intracellular levels of APP cleavage fragments and insitu-hybridization to visualize correlated expression of GGAs and BACE in rat brain. All three GGAs colocalize with BACE1 at perinuclear compartments. FLIM revealed a donor-lifetime decrease indicating interaction between all three GGAs and BACE. Control experiments with GGA and BACE mutants show that the VHS domain of the GGA proteins and the DXXLL-motive in the BACE protein are necessary for this interaction. Mutants of GGA1 and GGA3 which represent non-phosphorylated forms of these proteins showed decreased lifetime whereas autoinhibited pseudo-phosphorylated mutants reversed this. Elisa and Westernblotting revealed an increase of intracellular sAPP upon overexpression of any GGA. However a decrease in sAPP secretion was observed. This effect was neither reversible with Δ-VHS mutants nor with GGA1/3 phosphorylation-mutants.Insitu-hybridization revealed spatial and time correlated expression of GGAs and BACE in postnatal and adult rats. These results indicate that all GGAs have related functions on BACE interaction, controlled by concentration, location and phosphorylation. Beside the interaction with BACE, we suggest additional BACE-independent influence of GGAs on APP transport and processing, and therefore an essential role in APP cleavage and subsequent Abeta generation." @default.
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- W1988658526 date "2009-07-01" @default.
- W1988658526 modified "2023-09-27" @default.
- W1988658526 title "P2-141: Influence of GGA protein modifications on BACE interaction" @default.
- W1988658526 doi "https://doi.org/10.1016/j.jalz.2009.04.452" @default.
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