ubiquilin antagonizes presenilin and promotes neurodegeneration in Drosophila
UMass Chan Affiliations
Graduate School of Biomedical SciencesDocument Type
Journal ArticlePublication Date
2007-10-20Keywords
Alzheimer Disease; Animals; Carrier Proteins; Cell Cycle Proteins; Drosophila Proteins; Drosophila melanogaster; Humans; Presenilins; Retinal DegenerationLife Sciences
Medicine and Health Sciences
Metadata
Show full item recordAbstract
The majority of familial Alzheimer's disease (AD) cases are caused by mutations in presenilins, therefore, identifying regulators of presenilins is crucial for understanding AD pathogenesis. Ubiquilin 1 (UBQLN1) binds Presenilins in mammalian cells; however, the functional significance of this interaction in vivo remains unclear. Moreover, while genetic variants in UBQLN1 have recently been reported to associate with an increased risk for AD, whether these variants have altered function is unknown. Here, we show that Drosophila Ubiquilin (Ubqn) binds to Drosophila Presenilin (Psn), and that loss of ubqn function suppresses phenotypes that arise from loss of psn function in vivo. In addition, overexpression of ubqn in the eye results in adult-onset, age-dependent retinal degeneration, which is at least partially apoptotic in nature. The degeneration associated with ubqn overexpression can also be suppressed by psn overexpression and enhanced by expression of a dominant negative version of Psn. Remarkably, expression of the human AD-associated variant of UBQLN1 leads to more severe degeneration than does comparable expression of the human wildtype UBQLN1. Together, these data identify Ubqn as a regulator of Psn, support an important role for UBQLN1 in AD pathogenesis, and suggest the possibility that expression of a human AD-associated variant can cause neurodegeneration independent of amyloid production.Source
Hum Mol Genet. 2008 Jan 15;17(2):293-302. Epub 2007 Oct 18. Link to article on publisher's siteDOI
10.1093/hmg/ddm305Permanent Link to this Item
http://hdl.handle.net/20.500.14038/33720PubMed ID
17947293Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.1093/hmg/ddm305