Spinocerebellar Ataxia type 3 (SCA3), also known as Machado-Joseph disease, is one of at least nine diseases caused by CAG repeat expansions that encode abnormally long polyglutamine tracts in the disease proteins. Despite advances in disease understanding, much remains unknown about how the CAG expansion in the SCA3 disease gene, ATXN3, causes brain dysfunction and cell death. We recently discovered selective oligodendrocyte vulnerability across SCA3 mouse disease brain regions and identified early and robust changes that implicate oligodendrocytes in disease pathogenesis. Our long-term objective is to understand pathogenic mechanisms in SCA3 and related polyglutamine diseases so that therapies targeting the most promising molecular and cellular targets can be developed for these fatal and currently untreatable disorders. Toward that objective, the team of investigators will leverage their diverse research expertise and a wide range of model systems including primary cell cultures, mouse models, and human disease tissue. Building on recent discoveries in mouse models and human disease tissue, we will investigate nonneuronal contributions to disease pathogenesis, with an emphasis on cells of the oligodendroglial lineage. In Aim 1, we will determine how widespread oligodendrocyte dysfunction is in SCA3 disease. In Aim 2, we will generate novel conditional SCA3 mouse models to establish if the mutant protein elicits cell-autonomous oligodendrocyte dysfunction and define oligodendrocyte dysfunction contributions to disease pathogenesis. In Aim 3, we will elucidate the molecular mechanisms that underlie oligodendrocyte dysfunction in SCA3 disease. Results of these studies will help guide therapeutic development in SCA3 and related polyglutamine diseases.