Animal Models of Spinocerebellar Ataxia Type 1

Expansion of a polyglutamine repeat within the spinocerebellar ataxia type 1 (. SCA1)-encoded protein ataxin-1 (ATXN1) causes the neurodegenerative disease SCA1. Numerous animal models have been generated that recapitulate many aspects of SCA1 pathogenesis. Studies using these animal models have led to numerous conclusions regarding the pathogenic potential of mutant ATXN1. Although protein folding and clearance pathways are important in the development of disease, ATXN1 nuclear inclusion formation is not required for initiation of disease. In the case of SCA1, Purkinje cells are the last neurons to form nuclear inclusions but are the most susceptible to the toxic effects of mutant ATXN1, suggesting inclusion formation may be a protective event. Nuclear localization of mutant ATXN1 is necessary but not sufficient to induce pathogenesis. A single amino acid, serine 776, within ATXN1 was found to be important in disease progression. Serine 776 of both wild-type and mutant ATXN1 is phosphorylated. Preventing phosphorylation of this residue by replacing it with alanine results in a mutant protein found in the nucleus that is not pathogenic. Other modifiers of ATXN1-induced neurodegeneration include components of RNA processing, transcriptional regulators along with key genes misregulated in SCA1, and protein processing pathways. More important, SCA1 animal models are being tested in hypotheses-driven, disease-modifying therapies.