An increasing number of neurodegenerative disorders have been found to be caused 
by expanding CAG triplet repeats that code for polyglutamine. Huntington's 
disease (HD) is the most common of these disorders and 
dentatorubral-pallidoluysian atrophy (DRPLA) is very similar to HD, but is 
caused by mutation in a different gene, making them good models to study. In 
this review, we will concentrate on the roles of protein aggregation, nuclear 
localization and proteolytic processing in disease pathogenesis. In cell model 
studies of HD, we have found that truncated N-terminal portions of huntingtin 
(the HD gene product) with expanded repeats form more aggregates than longer or 
full length huntingtin polypeptides. These shorter fragments are also more prone 
to aggregate in the nucleus and cause more cell toxicity. Further experiments 
with huntingtin constructs harbouring exogenous nuclear import and nuclear 
export signals have implicated the nucleus in direct cell toxicity. We have made 
mouse models of HD and DRPLA using an N-terminal truncation of huntingtin (N171) 
and full-length atrophin-1 (the DRPLA gene product), respectively. In both 
models, diffuse neuronal nuclear staining and nuclear inclusion bodies are 
observed in animals expressing the expanded glutamine repeat protein, further 
implicating the nucleus as a primary site of neuronal dysfunction. Neuritic 
pathology is also observed in the HD mice. In the DRPLA mouse model, we have 
found that truncated fragments of atrophin-1 containing the glutamine repeat 
accumulate in the nucleus, suggesting that proteolysis may be critical for 
disease progression. Taken together, these data lead towards a model whereby 
proteolytic processing, nuclear localization and protein aggregation all 
contribute to pathogenesis.