SCA7 mouse models show selective stabilization of mutant ataxin-7 and similar cellular responses in different neuronal cell types

Accumulation of expanded polyglutamine proteins and selective pattern of ne uronal loss are hallmarks of at least eight neurodegenerative disorders, in cluding spinocerebellar ataxia type 7 (SCA7). We previously described SCA7 mice displaying neurodegeneration with progressive ataxin-7 accumulation in two cell types affected in the human pathology. We describe here a new tra nsgenic model with a more widespread expression of mutant ataxin-7, includi ng neuronal cell types unaffected in SCA7. In these mice a similar handling of mutant ataxin-7, including a cytoplasm to nucleus translocation and acc umulation of N-terminal fragments, was observed in all neuronal populations studied. An extensive screen for chaperones, proteasomal subunits and tran scription factors sequestered in nuclear inclusions (NIs) disclosed no patt ern unique to neurons undergoing degeneration in SCA7. In particular, we fo und that the mouse TAF(parallel to)30 subunit of the TFIID initiation compl ex is markedly accumulated in NIs, even though this protein does not contai n a polyglutamine stretch. A striking discrepancy between mRNA and ataxin-7 levels in transgenic mice expressing the wild-type protein but not in thos e expressing the mutant one, indicates a selective stabilization of mutant ataxin-7, both in this model and the P7E/N model described previously. Thes e mice therefore provide in vivo evidence that the polyglutamine expansion mutation can stabilize its target protein.