Polyglutamine pathogenesis

An increasing number of neurodegenerative disorders have been found to be c aused by expanding CAG tripler repeats that code for polyglutamine. Hunting ton's disease (HD) is the most common of these disorders and dentatorubral- pallidoluysian atrophy (DRPLA) is very similar to HD, but is caused by muta tion in a different gene, making them good models to study In this review, we will concentrate on the roles of protein aggregation, nuclear localizati on and proteolytic processing in disease pathogenesis. In cell model studie s of HD! we have found that truncated N-terminal portions of huntingtin (th e HD gene product) with expanded repeats form more aggregates than longer o r full length huntingtin polypeptides. These shorter fragments are also mor e prone to aggregate in the nucleus and cause more cell toxicity Further ex periments with huntingtin constructs harbouring exogenous nuclear import an d nuclear export signals have implicated the nucleus in direct cell toxicit y 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, res pectively In both models, diffuse neuronal nuclear staining and nuclear inc lusion bodies are observed in animals expressing the expanded glutamine rep eat protein, further implicating the nucleus as a primary site of neuronal dysfunction, Neuritic pathology is also observed in the HD mice. In the DRP LA mouse model, we have found chat truncated fragments of atrophin-1 contai ning the glutamine repeat accumulate in the nucleus, suggesting that proteo lysis may be critical for disease progression. Taken together, these data l ead towards a model whereby proteolytic processing, nuclear localization an d protein aggregation all contribute to pathogenesis.