Chapter K3 - Animal Models of Spinocerebellar Ataxia Type 1 (SCA1)

Abstract

Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant adult onset neurological disorder in which individuals typically survive only 10–15 years after the first appearance of symptoms. Clinically, SCA1 patients exhibit ataxia, dysarthria, and bulbar dysfunction. Pathologically, there is Purkinje cell loss in the cerebellar cortex and loss of neurons in the inferior olivary nuclei, cerebellar dentate nuclei, and the red nuclei. Other than the CAG repeat tract, the gene products associated with these disorders share no significant homology. A common feature among the polyglutamine diseases is the aberrant deposition of the mutant protein. Most often these accumulations are found within the nucleus of neurons. The role that nuclear inclusions play in disease pathogenesis remains controversial. Of particular interest is the cells pecificity of pathogenesis. Despite widespread expression of these proteins in the brain and other tissues, only a certain subset of neurons is vulnerable to neurodegeneration in each of the disorders. An important and relevant conclusion has come out of the numerous SCA1 transgenic mouse studies; the disease pathway appears to be acting through ataxin-1's normal cellular pathway. Thus, defining the role of phosphorylated ataxin-1 in the nucleus may provide further insights into SCA1 pathogenesis. To the date, the progress made in developing an understanding of the disease process in SCA1 has uncovered numerous potential sites for therapeutic intervention including upregulation of molecular chaperone or protein degradation pathways, regulation of subcellular localization, and altering the solubility of the mutant protein.