Machado-Joseph disease (MJD) is a neurodegenerative disease resulting in the loss of muscle control and coordination. This disease is caused by inheritance of the ATXN3 gene containing an expanded CAG trinucleotide repeat region encoding for the polyglutamine (polyQ) tract in the ataxin-3 protein. Normally, the length of the CAG repeat region is between 12-44 repeats whilst MJD patients harbour >44 repeats. There is no known treatment or cure to prevent disease progression and understanding the mechanisms causing MJD neuropathology are limited. Thus, there are various cell and animal models exploring potential mechanisms of disease and investigating which treatments could ameliorate disease phenotypes.
Our team has generated the first transgenic zebrafish model of MJD. Zebrafish are a popular animal model to investigate neurodegeneration due to external development of the embryos, for easy genetic manipulation and observation. The main advantage is the permeability of embryos, allowing for easy absorption of compounds dissolved in their environment. In combination with this, zebrafish embryos develop rapidly, allowing for high throughput drug testing. This thesis aimed to characterise disease phenotypes that develop in this zebrafish model and study these phenotypes to investigate disease mechanisms and potential treatments. Disease phenotypes identified within the zebrafish expressing human polyQ expanded ataxin-3 protein were motor impairment and ataxin-3 positive cleavage fragments. We monitored these phenotypes to explore a number of related pathways, including autophagy and transcription regulation, to understand how these pathways may relate to the development of the disease phenotypes. Finally, we tested whether a variety of small compounds/drugs are protective. The findings of this drug testing provided valuable insight towards the development of a treatment for MJD.