Identification of novel genes that modify phenotypes induced by Alzheimer's beta-amyloid overexpression in Drosophila.
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 beta-amyloid (Abeta) peptides, the complete network of interactions regulating Abeta metabolism and toxicity still eludes us. To address this, we have conducted genetic interaction screens using transgenic Drosophila expressing Abeta and we have identified mutations that affect Abeta 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 Abeta effects. Several of the mutations that we identified have not been linked to Abeta 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 Abeta and open new areas for further study into AD pathogenesis.
Cao
Weihuan
W
Novartis Institutes for Biomedical Research, Cambridge, Massachusetts 02139, USA.
Song
Ho-Juhn
HJ
Gangi
Tina
T
Kelkar
Anju
A
Antani
Isha
I
Garza
Dan
D
Konsolaki
Mary
M
D000544:Alzheimer Disease / Q000235:genetics*; D016229:Amyloid beta-Peptides / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D030801:Animals, Genetically Modified; D002784:Cholesterol / Q000378:metabolism; D002843:Chromatin / Q000737:chemistry / Q000378:metabolism; D029721:Drosophila Proteins / Q000378:metabolism; D004331:Drosophila melanogaster / Q000187:drug effects / Q000235:genetics*; D005123:Eye / Q000166:cytology / Q000187:drug effects; D017344:Genes, Insect; D006706:Homeostasis / Q000187:drug effects; D009154:Mutation / Q000235:genetics; D009420:Nervous System / Q000187:drug effects / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism; D010455:Peptides / Q000633:toxicity; D010641:Phenotype; D012995:Solubility / Q000187:drug effects; D016875:tau Proteins / Q000378:metabolism
D016229:Amyloid beta-Peptides; D002843:Chromatin; D029721:Drosophila Proteins; D010446:Peptide Fragments; D010455:Peptides; C075222:amyloid beta-protein (1-42); D016875:tau Proteins; C097188:polyglutamine; D002784:Cholesterol