Ataxin-3 is a ubiquitously expressed deubiqutinating enzyme with important 
functions in the proteasomal protein degradation pathway and regulation of 
transcription. The C-terminus of the ataxin-3 protein contains a polyglutamine 
(PolyQ) region that, when mutationally expanded to over 52 glutamines, causes 
the neurodegenerative disease spinocerebellar ataxia 3 (SCA3). In spite of 
extensive research, the molecular mechanisms underlying the cellular toxicity 
resulting from mutant ataxin-3 remain elusive and no preventive treatment is 
currently available. It has become clear over the last decade that the hallmark 
intracellular ataxin-3 aggregates are likely not the main toxic entity in SCA3. 
Instead, the soluble PolyQ containing fragments arising from proteolytic 
cleavage of ataxin-3 by caspases and calpains are now regarded to be of greater 
influence in pathogenesis. In addition, recent evidence suggests potential 
involvement of a RNA toxicity component in SCA3 and other PolyQ expansion 
disorders, increasing the pathogenic complexity. Herein, we review the 
functioning of ataxin-3 and the involvement of known protein and RNA toxicity 
mechanisms of mutant ataxin-3 that have been discovered, as well as future 
opportunities for therapeutic intervention.