Isolation and characterization of the Drosophila ubiquilin ortholog dUbqln : in vivo interaction with early-onset Alzheimer disease genes

Abstract

UBQLN1 variants have been associated with increased risk for late-onset Alzheimer’s disease (AD). We produced transgenic Drosophila models that either silence (by RNAi) or overexpress the Drosophila ortholog of human UBQLN1 , dUbqln . Silencing of dUbqln in the central nervous system led to age-dependent neurodegeneration and shortened lifespan. Silencing of dUbqln in the wing led to wing vein loss that could be partially rescued by mutant rhomboid ( rho ), a known component of epidermal growth factor receptor signaling pathway. Conversely, overexpression of dUbqln promoted ecotopic wing veins. Overexpression of dUbqln in the eye rescued a small, rough eye phenotype induced by overexpression of Drosophila presenilin (dPsn) , and also rescuing dPsn -induced malformations in bristles. In contrast, RNAi silencing of dUbqln enhanced the retinal degenerative defect induced by overexpression of dPsn . Finally, co-overexpression of dUbqln and the human amyloid precursor protein ( APP ) in the eye significantly reduced the levels of full-length APP and its C-terminal fragment. Collectively, these data support in vivo functional interaction between UBQLN1 and the AD-associated genes, presenilin and APP , and provide further clues regarding the potential role of UBQLN1 in AD pathogenesis.