Spinocerebellar ataxia type 3 is a neurodegenerative disorder caused by the 
expansion of the polyglutamine repeat region within the ataxin-3 protein. The 
mutant protein forms intracellular aggregates in the brain. However, the 
cellular mechanisms causing toxicity are still poorly understood and there are 
currently no effective treatments. In this study we show that administration of 
a rapamycin ester (cell cycle inhibitor-779, temsirolimus) improves motor 
performance in a transgenic mouse model of spinocerebellar ataxia type 3. 
Temsirolimus inhibits mammalian target of rapamycin and hence upregulates 
protein degradation by autophagy. Temsirolimus reduces the number of aggregates 
seen in the brains of transgenic mice and decreases levels of cytosolic soluble 
mutant ataxin-3, while endogenous wild-type protein levels remain unaffected. 
Temsirolimus is designed for long-term use in patients and therefore represents 
a possible therapeutic strategy for the treatment of spinocerebellar ataxia type 
3. Using this disease model and treatment paradigm, we employed a microarray 
approach to investigate transcriptional changes that might be important in the 
pathogenesis of spinocerebellar ataxia type 3. This identified ubiquitin 
specific peptidase-15, which showed expression changes at both the messenger 
ribonucleic acid and protein level. Ubiquitin specific peptidase-15 levels were 
also changed in mice expressing another mutant polyglutamine protein, 
huntingtin. In total we identified 16 transcripts that were decreased in 
transgenic ataxin-3 mice that were normalized following temsirolimus treatment. 
In this mouse model with relatively mild disease progression, the number of 
transcripts changed was low and the magnitude of these changes was small. 
However, the importance of these transcriptional alterations in the pathogenesis 
of spinocerebellar ataxia type 3 remains unclear.