In 1999 we isolated the SCA8 expansion mutation from a single ataxia patient by RAPID cloning and subsequently found the expansion in additional ataxia families including a seven generation kindred (lod 6.8, -=0.0). The reduced penetrance of the disease and the demonstration that SCA8 expansions are also found in the general population have generated controversy in the field and led to the suggestions that either the expansion is not pathogenic or that additional genetic or environmental factors strongly affect penetrance. To further characterize the disease and to test the pathogenic properties of the SCA8 expansion we have studied a large panel of SCA8 families and have developed transgenic murine models. Our SCA8 BAG expansion.mice develop a progressive, severe, neurological phenotype characterized by the following pathogenic changes: 1) in vivo optical imaging studies demonstrate cerebellar dysfunction of the parallel fiber-Purkinje cell circuit (with reduced GABA-ergic inhibition); 2) 1C2 and ubiquitin-positive intranuclear inclusions are found in Purkinje cells and pontine neurons with similar findings in human SCA8 autopsy tissue; 3) specific alternative splicing changes are found in SCA8 BAG expansion mice and human autopsy tissue, suggesting the CUG expansion transcripts play a role in disease pathogenesis through an RNA-gain-of-function mechanism. We propose studies to further characterize the molecular pathogenesis of SCA8 and the potential reversibility of the disease.
Our specific aims are:
Aim 1) To further characterize the distribution of the SCA8 inclusions and the alternative splicing changes in human autopsy tissue and our BAG transgenic mice;
Aim 2) To further define the functional deficits in cerebellar inhibition found in our SCA8 BAG transgenic model and compare this model with a second PCP2-expansion model in which a truncated SCA8 cDNA is expressed in Purkinje cells;
Aim 3) To develop cell culture models of SCA8 to separately test RNA and protein gain of function models and to evaluate the contributions that expressionof the expansion at the RNA and protein levels play on inclusion formation and in disease specific dysregulation of alternative splicing;
Aim 4) To develop a reversible BAG transgenic model of SCA8 to determine if aspects of the phenotype in our murine models can be prevented or reversed by removing the CTG expansion mutation using Cre-recombinase.
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