Basic HTML Version
Full Abstracts – DROSOPHILA MODELS OF HUMAN DISEASE
125
17
Genome-wide Association Mapping of Resistance to Oxidative Stress in
Drosophila
Identifies Genes Involved in Complex Disease.
Allison L.
Weber
1,2
, George F. Khan
2,3
, Michael M. Magwire
1
, Crystal L. Tabor
1
, Robert R. H. Anholt
1,2,3
, Trudy F. C. Mackay
1,2
. 1) Department of Genetics, North
Carolina State University, Raleigh, NC; 2) W. M. Keck Center for Behavioral Biology, North Carolina State University, Raleigh, NC; 3) Department of
Biology, North Carolina State University, Raleigh, NC.
Oxidative stress has been implicated in ageing, the progression of cardiovascular and neurodegenerative diseases in humans and the disruption of cell
signaling processes that control cell growth and death. Although several genes involved in cellular responses to oxidative stress have been identified there is
limited knowledge concerning how natural genetic variation contributes to variation in resistance to oxidative stress. In order to identify these genes, we
have recently completed genome-wide association mapping of acute oxidative stress resistance in a panel of 167 inbred wild-derived
Drosophila
lines. We
assessed oxidative stress resistance for all lines by measuring survival times on exposure to 20mM paraquat and 75mM menadione sodium bisulfite. We
found significant genetic variation, and genetic variation for sexual dimorphism under both treatment conditions. We detected 298 SNPs significantly
associated with resistance to paraquat and 146 SNPs significantly associated with resistance to menadione sodium bisulfite. Among these associations,
variation in only seven genes was significantly associated with resistance to both paraquat and menadione sodium bisulfite. Approximately half of the genes
identified have human homologs and a quarter have previously been implicated in complex diseases. These results suggest that the genetic architecture of
oxidative stress resistance is sex-specific and dependent on the method of induction. This study illustrates the potential of using the genetically tractable,
easily manipulated
Drosophila
system to identify human candidate genes that may harbor risk alleles to oxidative stress dependent complex human diseases,
including neurodegenerative disorders such as Parkinson’s disease.
18
ATM kinase inhibition in glial cells activates the innate immune response and causes neurodegeneration.
Andrew Petersen, David Wassarman.
Cellular and Regenerative Biology, University of Wisconsin-Madison, Madison, WI.
To investigate the mechanistic basis for central nervous system (CNS) neurodegeneration in the childhood disease Ataxia-telangiectasia (A-T), we
analyzed flies mutant for the causative gene A-T mutated (ATM). ATM encodes a protein kinase that functions to monitor the genomic integrity of cells and
control cell cycle and DNA repair programs. Mutation of the C-terminal amino acid in Drosophila ATM inhibited the kinase activity and caused neuronal
and glial cell death in the adult fly brain and a significant reduction in longevity. These data suggest that loss of kinase activity is sufficient to cause
neurodegeneration in A-T. ATM kinase mutant flies also exhibited prolonged upregulation of a transcription program in glial cells consistent with activation
of the innate immune response. ATM knockdown specifically in glial cells was sufficient to cause neuronal and glial cell death, activation of the glial cell
innate immune response, and a significant reduction in longevity, indicating that non-cell autonomous toxicity contributes to neurodegeneration in A-T.
Taken together, these data suggest that early onset CNS neurodegeneration in A-T is similar to late onset CNS neurodegeneration in diseases such as
Alzheimer’s wherein uncontrolled inflammatory response mediated by glial cells drives progressive neurodegeneration. Current experiments are focused on
elucidating the specific glial subtype initiating the immune response, as well as the signaling pathways responsible for immune gene expression.
19
A Drosophila Model Linking Diet-induced Metabolic Disease and Cancer.
Susumu Hirabayashi
1
, Thomas Baranski
2
, Ross Cagan
1
. 1) Mount Sinai
School of Medicine, New York, NY; 2) Washington University School of Medicine, St. Louis, MO.
Epidemiological studies have demonstrated that increased cancer risk is associated with metabolic disease including obesity and diabetes, but the
underlying mechanism remains poorly understood. To this end, we have developed whole animal Drosophila cancer models that permit us to explore tumor
progression in 'diabetic' flies. Feeding Drosophila a diet high in carbohydrates was previously demonstrated to direct metabolic dysfunction including
insulin-resistance, hyperglycemia, increased insulin levels, and accumulation of fat. We now show that high dietary sugar also transforms Ras/Src-activated
tissue from localized growths to aggressive tumors with emergent metastases. Surprisingly, while most tissues displayed aspects of metabolic dysfunction
including insulin resistance, Ras/Src-activated tumors retained insulin pathway sensitivity and exhibited an increased ability to import glucose as well as
resistance to apoptotic elimination. We provide evidence that this reflects increased Insulin signaling, which in turn acts through Wingless/Wnt signaling to
promote diet-mediated malignant phenotypes within Ras/Src-activated tumors. These fly models should provide useful paradigms to study the link between
metabolic dysfunction and tumorigenesis in the context of a whole animal.