Spinal and bulbar muscular atrophy (SBMA) is a slowly progressive X-linked neuromuscular disease, for which there is no cure or therapy. Arising in adult males, it is phenotypically characterized by proximal limb and bulbar muscle weakness, fasciculations, and muscle atrophy, caused by dysfunction and degeneration of lower motor neurons and skeletal muscle. The purpose of this project is to generate a more cost-effective, high- throughput, and disease relevant in vivo model system of SBMA, using zebrafish. Support for zebrafish as a disease relevant model of SBMA includes the high structural homology of human and zebrafish neuroanatomy and muscle physiology. Moreover, zebrafish, unlike their small research animal counterparts, flies and worms, express an androgen receptor (AR), and this AR is similar in structure and function to human AR, indicating that the zebrafish, in addition to the fact that it is a vertebrate, would serve as a superior high-throughput model of SBMA. As the disease causing mutation in SBMA is a polyglutamine expansion in the AR protein, we aim to generate a transgenic lines of zebrafish that express polyglutamine-expanded AR, as well as the control, normal glutamine length AR. We postulate that male zebrafish expressing polyglutamine-expanded AR will manifest motor function deficits and histopathology similar to those observed in mouse models and SBMA patients. A zebrafish model of SBMA would provide a powerful, inexpensive, vertebrate model to complement current animal models and expedite therapeutic development for this patient population.
There is currently no cure or therapy for the neuromuscular disease spinal and bulbar muscular atrophy (SBMA). Zebrafish represent a powerful, inexpensive, high-throughput vertebrate animal to investigate therapeutic approaches for human disease. We will create and characterize a zebrafish model of SBMA to expedite therapeutic development for this patient population.