Spinocerebellar Ataxia Type 1: Lessons From Modeling a Movement Disease in Mice

Expansion of a polyglutamine repeat within the spinocerebellar ataxia type 1 (SCA1)-encoded protein, ataxin-1, causes the neurodegenerative disease, SCA1. Animal models have been generated that recapitulate many of the aspects of SCA1 pathogenesis. These provide a good example of how animal models can be used to examine the pathogenesis of a human neurological disease. Studies using these animal models have led to numerous conclusions regarding the pathogenic potential of mutant ataxin-1. The data indicate that protein folding and clearance pathways are important in the development of disease. Aggregation of mutant ataxin-1 is not required for initiation of disease. In the case of SCA1, Purkinje cells are the last neurons to aggregate the mutant protein but the most susceptible to the toxic effects of mutant ataxin-1, suggesting that aggregation may be a protective event. Nuclear localization of mutant ataxin-1 is necessary but not sufficient to induce pathogenesis. A single amino acid, serine 776, within ataxin-1 was found to be important in disease progression. Serine 776 of both wild-type and mutant ataxin-1 is phosphorylated. Preventing phosphorylation of this residue by replacing it with an alanine results in a mutant protein found in the nucleus that is not pathogenic. Other modifiers of ataxin-1-induced neurodegeneration include components of RNA-processing and protein-processing pathways. Importantly, because wild-type ataxin-1 is found in the nucleus and is phosphorylated at serine 776, the disease pathway likely overlaps with the normal cellular pathway(s) in which ataxin-1 participates.