Originally published as Genetics Published Articles Ahead of Print on February 3, 2008.

Genetics, Vol. 178, 1457-1471, March 2008, Copyright © 2008
doi:10.1534/genetics.107.078394

Identification of Novel Genes That Modify Phenotypes Induced by Alzheimer's β-Amyloid Overexpression in Drosophila

Weihuan Cao*, Ho-Juhn Song{dagger}, Tina Gangi*, Anju Kelkar{dagger}, Isha Antani*, Dan Garza{dagger} and Mary Konsolaki*,1

* Department of Genetics, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854 and {dagger} Novartis Institutes for Biomedical Research, Cambridge, Massachusetts 02139

1 Corresponding author: Department of Genetics, Rutgers, The State University of New Jersey, Piscataway, NJ 08854.
E-mail: konsolaki{at}biology.rutgers.edu

Sustained increases in life expectancy have underscored the importance of managing diseases with a high incidence in late life, such as various neurodegenerative conditions. Alzheimer's disease (AD) is the most common among these, and consequently significant research effort is spent on studying it. Although a lot is known about the pathology of AD and the role of β-amyloid (Aβ) peptides, the complete network of interactions regulating Aβ metabolism and toxicity still eludes us. To address this, we have conducted genetic interaction screens using transgenic Drosophila expressing Aβ and we have identified mutations that affect Aβ metabolism and toxicity. These analyses highlight the involvement of various biochemical processes such as secretion, cholesterol homeostasis, and regulation of chromatin structure and function, among others, in mediating toxic Aβ effects. Several of the mutations that we identified have not been linked to Aβ toxicity before and thus constitute novel potential targets for AD intervention. We additionally tested these mutations for interactions with tau and expanded-polyglutamine overexpression and found a few candidate mutations that may mediate common mechanisms of neurodegeneration. Our data offer insight into the toxicity of Aβ and open new areas for further study into AD pathogenesis


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Genetics 2008 178: NP. [Full Text]