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Abstract

Ubiquilin-1 is an Alzheimer's disease-associated protein, which is known to modulate amyloid precursor protein (APP) processing, amyloid-beta (A beta) secretion, and presenilin-1 (PS1) accumulation. Here, we aim to elucidate the molecular mechanisms by which full-length transcript variant 1 of ubiquilin-1 (TV1) affects APP processing and gamma-secretase function in human neuroblastoma cells stably overexpressing APP (SH-SY5Y-APP751). We found that TV1 overexpressing significant increased the level of APP intracellular domain (AICD) generation. However, there was no increase in the levels of secreted A beta 40, A beta 42, or total A beta, suggesting that ubiquilin-1 in particular enhances gamma-secretase-mediated epsilon-site cleavage. This is supported by the finding that TV1 also significantly increased the level of intracellular domain generation of another gamma-secretase substrate, leukocyte common antigen-related (LAR) phosphatase. However, in these cells, the increase in AICD levels was abolished, suggesting a preference of the gamma-secretase for LAR over APP. TV2, another ubiquilin-1 variant that lacks the protein fragment encoded by exon 8, did not increase the level of AICD generation like TV1 did. The subcellular and plasma membrane localization of APP or gamma-secretase complex components PS1 and nicastrin was not altered in TV1-overexpressing cells. Moreover, the effects of TV1 were not mediated by altered expression or APP binding of FE6S, an adaptor protein thought to regulate AICD generation and stability. These data suggest that ubiquilin-1 modulates gamma-secretase-mediated epsilon-site cleave and thus may play role in regulating gamma-secretase cleavage of various substrates.