Mutant ataxin-3 is aberrantly folded and proteolytically cleaved in 
spinocerebellar ataxia type 3. The C-terminal region of the protein includes a 
polyglutamine stretch that is expanded in spinocerebellar ataxia type 3. Here, 
we report on the analysis of an ataxin-3 mutant mouse that has been obtained by 
gene trap integration. The ataxin-3 fusion protein encompasses 259 N-terminal 
amino acids including the Josephin domain and an ubiquitin-interacting motif but 
lacks the C-terminus with the polyglutamine stretch, the valosin-containing 
protein binding region and part of the ubiquitin-interacting motif 2. Homozygous 
ataxin-3 mutant mice were viable and showed no apparent anatomical defects at 
birth. However, at the age of 9 months, homozygous and heterozygous mutant mice 
revealed significantly altered behaviour and progressing deficits of motor 
coordination followed by premature death at ∼12 months. At this time, prominent 
extranuclear protein aggregates and neuronal cell death was found in mutant 
mice. This was associated with disturbances of the endoplasmic 
reticulum-mediated unfolded protein response, consistent with the normal role of 
ataxin-3 in endoplasmic reticulum homeostasis. Thus, the ataxin-3 gene trap 
model provides evidence for a contribution of the non-polyglutamine containing 
ataxin-3 N-terminus, which mimics a calpain fragment that has been observed in 
spinocerebellar ataxia type 3. Consistent with the disease in humans, gene trap 
mice develop cytoplasmic inclusion bodies and implicate impaired unfolded 
protein response in the pathogenesis of spinocerebellar ataxia type 3.