Taylor Lab Research

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The basis of ligand-dependent neurodegeneration in SBMA
	Spinobulbar muscular atrophy (SBMA) is an inherited motor neuron disease caused by CAG/polyglutamine expansion in the androgen receptor. Eight other inherited neurodegenerative diseases are caused by the same type of mutation, including Huntington’s disease and a number of spinocerebellar ataxias. An interesting feature that distinguishes SBMA is that only men are affected, due to hormone-dependent toxicity of the mutant androgen receptor. The conditional nature of the neurotoxicity in SBMA provides unique opportunities for empirical studies examining how neurons cope with toxic proteins in general and the mechanism of polyglutamine-mediated neurodegeneration in particular. We have developed a Drosophila model that closely recapitulates the ligand-dependent and polyglutamine length-dependent neurodegeneration seen in SBMA. We are using this reagent to test hypotheses regarding polyglutamine toxicity, such as impairment of the UPS and disruption of a transcription co-activator complex. We are also using the SBMA model in hypothesis-generating studies, including a dominant modifier screen of the fly genome.



	*A Drosophila* model of SBMA. Expression of human AR results in ligand-dependent, polyQ length-dependent degeneration. Flies not treated with DHT have normal eyes (top row). Flies reared on food containing DHT show polyQ length-dependent degeneration (bottom row**). Degeneration is most severe at the posterior eye margin. There is disorganization of the ommatidial array, fusion of ommatidia, and abnormal bristles. Longer repeat length causes a more severe degenerative phenotype that extends further anteriorly. Ligand-dependent, polyQ length-dependent degeneration recapitulates two key features of human SBMA. >1000 fly eyes of each genotype have been examined.



	Motor neuron expression of polyglutamine-expanded AR causes a ligand-dependent locomotor defect. Negative geotaxis is a natural instinct in Drosophila that is frequently used to examine the robustness of locomotor function. The movie above shows how this instinct is exploited in our behavioral climbing assay. In this assay, the climbing performance of flies is used to quantify the effect of polyglutamine-expanded AR expression on locomotor function. Flies expressing polyglutamine-expanded AR in motor neurons were placed either on normal food (left) or food laden with DHT (right) on day 1 of adulthood, a paradigm that parallels the adult onset of SBMA. The climbing ability of these flies was recorded on day 30, revealing a ligand-dependent locomotor defect.