Polyglutamine expansion down-regulates specific neuronal genes before pathologic changes in SCA1

The expansion of an unstable CAG repeat causes spinocerebellar ataxia type 1 (SCA1) and several other neurodegenerative diseases. How polyglutamine ex pansions render the resulting proteins toxic to neurons, however, remains e lusive. Hypothesizing that long polyglutamine tracts alter gene expression, we found certain neuronal genes involved in signal transduction and calciu m homeostasis sequentially downregulated in SCA1 mice. These genes were abu ndant in Purkinje cells, the primary site of SCA1 pathogenesis; moreover, t heir downregulation was mediated by expanded ataxin-1 and occured before de tectable pathology. Similar downregulation occurred in SCA1 human tissues. Altered gene expression may be the earliest mediator of polyglutamine toxic ity.