Isolation and characterization of the Drosophila ubiquilin ortholog dUbqln: in vivo interaction with early-onset Alzheimer disease genes.
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.
Li
Airong
A
Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Diseases, Department of Neurology, Massachusetts General Hospital and Harvard Medical school, Charlestown, MA 02128, USA.
Xie
Zhongcong
Z
Dong
Yuanlin
Y
McKay
Kenneth M
KM
McKee
Mary L
ML
Tanzi
Rudolph E
RE
D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D030801:Animals, Genetically Modified; D019521:Body Patterning / Q000235:genetics; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D004330:Drosophila / Q000235:genetics / Q000254:growth & development / Q000378:metabolism*; D029721:Drosophila Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D053763:Presenilins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D012160:Retina / Q000737:chemistry / Q000378:metabolism; D014921:Wings, Animal / Q000196:embryology
D016564:Amyloid beta-Protein Precursor; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D029721:Drosophila Proteins; D053763:Presenilins; C106427:Psn protein, Drosophila; C525176:Ubqn protein, Drosophila