2005 - 2004 Research
Drosophila melanogaster (fruitfly) model system
KDA funded research grant update - The KDA funded a grant to J. Paul Taylor, MD PhD at University of Pennsylvania for $25,000 in November 2003 for a Drosophila melanogaster (fruitfly) model system to investigate the molecular pathogenesis of Spinal and Bulbar Muscular Atrophy. Dr. Taylor has provided us with an update as to how their research is coming along.
Research update as of June 2004
J. Paul Taylor, MD, PhD University of Pennsylvania
$25,000 Grant Awarded November 2003: Drosophila melanogaster (fruitfly) model system to investigate the molecular pathogenesis of Spinal and Bulbar Muscular Atrophy
I'd like to provide an update on our Kennedy's disease research. We've made substantial headway in our characterization of the phenotype as reflected by locomotor activity and lifespan. We're now getting set to examine the histopathology using several different techniques. In addition, we have started creating a series of new transgenic Drosophila lines to extend the utility of the model. Specifically, we think that the Drosophila model provides a good system to test ideas raised by Dr. Lisa Ellerby of the Buck Institute and Dr. Andy Lieberman of the University of Michigan.
First, in collaboration with Dr. Ellerby, we will investigate the role of androgen receptor cleavage in the process of motor neuron toxicity. As you may recall her describing at past KDA meetings, Dr. Ellerby's work suggests that polyglutamine-expanded androgen receptor becomes toxic only after cleavage (cutting the protein into fragments). It is hypothesized that this cleavage event results in the formation of a toxic protein fragment. If it can be verified that cleavage is a requisite step in pathogenesis, preventing this cleavage may be a useful therapeutic strategy. Dr. Ellerby will be providing several "non-cleavable" forms of androgen receptor that we will use to make transgenic flies. If the cleavage hypothesis is correct, these flies may not show as much degeneration as the flies we are working with currently.
Second, in collaboration with Dr. Lieberman, we will investigate the role of chemical modification of the androgen receptor in the process of motor neuron toxicity. Dr. Lieberman recently published an excellent article describing a role for acetylation in aggregation of the androgen receptor (Thomas et al. J. Biol. Chem., Vol. 279, Issue 9, 8389-8395). Similar to the work by Dr. Ellerby, this suggests that features of the androgen receptor other than the polyglutamine repeat may be important determinants of toxicity. If it can be verified that acetylation of the androgen receptor (a chemical modification) influences toxicity, this may also provide a therapeutic strategy. Dr. Lieberman will be providing a "non-acetylatable" form of the androgen receptor that we will use to make transgenic flies. If this acetylation is an important step in pathogenesis, this should be reflected in the severity of degeneration in these flies.
-- J. Paul Taylor, MD, PhD