Machado-Joseph disease (MJD, also known as spinocerebellar ataxia type 3, SCA3), 
an autosomal dominant neurological disorder, is caused by an abnormal expanded 
polyglutamine (polyQ) repeat in the ataxin-3 protein. The length of the expanded 
polyQ stretch correlates positively with the severity of the disease and 
inversely with the age at onset. To date, we cannot fully explain the mechanism 
underlying neurobiological abnormalities of this disease. Yet, accumulating 
reports have demonstrated the functions of ataxin-3 protein in the chaperone 
system, ubiquitin-proteasome system, and aggregation-autophagy, all of which 
suggest a role of ataxin-3 in the clearance of misfolded proteins. Notably, the 
SCA3 pathogenic form of ataxin-3 (ataxin-3(exp)) impairs the misfolded protein 
clearance via mechanisms that are either dependent or independent of its 
deubiquitinase (DUB) activity, resulting in the accumulation of misfolded 
proteins and the progressive loss of neurons in SCA3. Some drugs, which have 
been used as activators/inducers in the chaperone system, ubiquitin-proteasome 
system, and aggregation-autophagy, have been demonstrated to be efficacious in 
the relief of neurodegeneration diseases like Huntington's disease (HD), 
Parkinson's (PD), Alzheimer's (AD) as well as SCA3 in animal models and clinical 
trials, putting misfolded protein clearance on the list of potential therapeutic 
targets. Here, we undertake a comprehensive review of the progress in 
understanding the physiological functions of ataxin-3 in misfolded protein 
clearance and how the polyQ expansion impairs misfolded protein clearance. We 
then detail the preclinical studies targeting the elimination of misfolded 
proteins for SCA3 treatment. We close with future considerations for translating 
these pre-clinical results into therapies for SCA3 patients.