Toward Understanding the Polyglutamine Disorder Spinocerebellar Ataxia Type 3 Using Mouse Models of Disease

Abstract

The polyglutamine (polyQ) diseases, including Spinocerebellar Ataxia type 3 (SCA3), are inherited neurodegenerative diseases caused by glutamine-encoding CAG expansions in disease genes. All polyQ diseases exhibit accumulation and aggregation of the disease protein in affected brain regions, yet central questions remain regarding the pathogenesis of these untreatable disorders, including which factors can influence disease protein aggregation, the extent to which aggregation drives disease, and the processes by which aggregation might contribute to toxicity. My thesis addresses these questions in a novel knock-in mouse model of SCA3. Chapter 1 reviews central features of polyQ disease, the use of knock-in mouse models to study polyQ disease, and aspects of SCA3. Chapter 2 provides the materials and methods used for the dissertation. Chapter 3 describes the generation and characterization of a SCA3 knock-in mouse model. SCA3 knock-in mice show striking mutant ATXN3 accumulation and aggregation in brain. This accompanies aberrant splicing of the mutant Atxn3 transcript, emulating an important feature of the human ATXN3 transcript. Chapter 4 further explores how alternative Atxn3 splicing influences aggregation in a “variant” SCA3 knock-in mouse that exhibits minimal aggregate pathology. Using various mouse models I explore the relationship between mutant ATXN3 aggregation and transcriptional alterations in the pons, a susceptible brain region. Chapter 5 concludes the dissertation with thoughts regarding moving forward with this work. This thesis establishes the utility of SCA3 knock-in mice for studying early molecular pathogenic events and provides evidence supporting a critical role for alternative splicing in influencing disease protein aggregation. The results further suggest a molecular link between the process of ATXN3 aggregation and transcriptional dysregulation in the brain. Together, these findings support a pathogenic role for disease protein aggregation in SCA3 and perhaps other polyQ diseases.