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A reporter for amyloid precursor protein γ-secretase activity in Drosophila

Guo, Ming and Hong, Elizabeth J. and Fernandes, Jolene and Zipursky, S. Larry and Hay, Bruce A. (2003) A reporter for amyloid precursor protein γ-secretase activity in Drosophila. Human Molecular Genetics, 12 (20). pp. 2669-2678. ISSN 0964-6906. doi:10.1093/hmg/ddg292.

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A key event in the pathogenesis of Alzheimer's disease (AD) is the deposition of senile plaques consisting largely of a peptide known as β-amyloid (Aβ) that is derived from the amyloid precursor protein (APP). A proteolytic activity called γ-secretase cleaves APP in the transmembrane domain and is required for Aβ generation. Aberrant γ-secretase cleavage of APP underlies the majority of early onset, familial AD. γ-Secretase resides in a large multi-protein complex, of which Presenilin, Nicastrin, APH-1 and PEN-2 are four essential components. Thus, identifying components and pathways by which the γ-secretase activity is regulated is crucial to understanding the mechanisms underlying AD pathogenesis, and may provide new diagnostic tools and therapeutic targets. Here we describe the generation of Drosophila that act as living reporters of γ-secretase activity in the fly eye. In these reporter flies the size of the eye correlates with the level of endogenous γ-secretase activity, and is very sensitive to the levels of three genes required for APP γ-secretase activity, presenilin, nicastrin and aph-1. Thus, these flies provide a sensitized system with which to identify other components of the γ-secretase complex and regulators of its activity. We have used these flies to carry out a screen for mutations that suppress γ-secretase activity and have identified a small chromosomal region that contains a gene or genes whose products may promote γ-secretase activity.

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Additional Information:© 2003 Oxford University Press. Received June 18, 2003; Revised and Accepted August 16, 2003. First published online: August 27, 2003. We thank John Nambu, Gary Struhl and Mark Fortini for the gift of fly stocks, the Bloomington Drosophila Stock Center for the deficiency kit, George Jackson for demonstrating the SEM technique and Hong Yu for technical assistance. M.G. wishes to thank members of the Zipursky laboratory and Daniel Geschwind for helpful discussions, Robert Collins for his encouragement and support and Ruilan Wang for her support and assistance with fly work. This work was supported by the National Institute of Health Career Development Award (KO8, NS 42580), the John Douglas French Alzheimer’s Foundation Fellowship, the UCLA Alzheimer Disease Research Center Pilot Grant and the Giannini Family Foundation Fellowship to M.G., and by grants from the Burroughs Wellcome Fund (New Investigator award in Pharmacological Sciences) and the Ellison Medical Foundation to B.A.H.
Funding AgencyGrant Number
NIHKO8 NS 42580
John Douglas French Alzheimer’s FoundationUNSPECIFIED
UCLA Alzheimer Disease Research Center Pilot GrantUNSPECIFIED
Giannini Family Foundation FellowshipUNSPECIFIED
Burroughs Wellcome FundUNSPECIFIED
Ellison Medical FoundationUNSPECIFIED
Issue or Number:20
Record Number:CaltechAUTHORS:20111017-105733837
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:27249
Deposited By: Tony Diaz
Deposited On:18 Oct 2011 20:58
Last Modified:09 Nov 2021 16:47

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