Polyglutamine (polyQ) expansion diseases are late-onset disorders that cause neurodegeneration through what has been shown to be toxicity of the polyglutamine stretch. In Spinocerebellar Ataxia, or SCAs, these affect thousands of patients in the U.S. and the prognosis is poor. As these ataxias progress for years-even decades-the health burden and suffering experienced by those affected are significant. Despite knowing the causative factor and the genes in which these expanded glutamines reside, understanding the mechanism of action for these toxic proteins is still unclear and a matter of intense debate. Some have argued nuclear inclusion and nuclear import are important. Others argue there is cytoplasmic clogging that is blocking the passage of necessary cargo. Even the issue of whether it is an RNA-based mechanism or a protein-based mechanism that causes toxicity is strongly debated (reviewed in Orr, HT 2012). Recently, it was observed in a Drosophila courtship circuit that expression of a SCA fragment containing an expansion in its polyglutamine residues led to behavioral anomalies. This anomaly might be the result of early neuronal loss or decay. Because death or dysfunction in this courtship circuit led to decreases in mating ability, its use as the basis for a behavioral screen for recovery presented itself. In pursuit of the goal to identify suppressors of behavioral anomalies in courtship, this research group will pursue two aims.
The first aim i s to identify the mechanism leading to aberrant courtship, determine whether it is cell death-based or cellular dysfunction-based, and whether activity can alter its sensitivity.
The second aim i s to develop a screen from polyQ-induced declines in mating ability in order to develop a mating screen for suppressors of a behavior. An exciting prospect brought about by developing a behavioral screen is the possibility that it might identify suppressors that act very early in the toxic process. Orr HT Cell biology of spinocerebellar ataxia J Cell Biol. Apr 16 2012;197(2):167---177.
The proposed study aims to increase our understanding of what occurs anatomically and functionally in a circuit that behaves abnormally when expressing toxic polyQ proteins. This understanding will then be used to develop behavioral screens to identify genetic suppressors of toxic polyQ expression. As the proposed studies will identify the genetic targets, these new targets can become the focus for developing pharmacological therapies. The screen itself can become a means to identify pharmacological suppressors of toxicity.