Understanding SCA1 pathogenesis in human cerebellar organoids

PROJECT SUMMARY/ABSTRACT Spinocerebellar ataxia type 1 (SCA1) is a dominantly inherited lethal neurodegenerative disease caused by 39- 82 CAG repeats in the ATAXIN-1 (ATXN1) gene. Patients with SCA1 suffer from progressive gait and balance deficits, and severe degeneration of Purkinje cells (PCs) in the cerebellum. There are no effective disease modifying therapies currently available for SCA1, indicating a critical need for better understanding of disease pathogenesis. Studies using limited postmortem brain tissue from patients are complicated by practical and ethical concerns of tissue availability, late disease stage with the loss of neurons, and manipulation. Mouse models of SCA1 have been extremely useful in increasing our understanding of SCA1, but have important limitations due to the inherent species differences as well as genetic modifications, such as overexpression and much longer CAG expansions than seen in patients, needed to model disease. Because of these limitations, we propose to complement studies using mouse models with the investigations of human cells, including models of the human cerebellum. Recent study developed a robust and reproducible protocol to generate human cerebellar organoids from iPSCs. We propose to use this protocol and our iPSCs lines from SCA1 patients and sibling controls to establish a human cerebellar organoid model of SCA1. This human cerebellar organoid SCA1 model will enable us to determine how ATXN1 with CAG expansions commonly seen in patients impacts human cerebellar cells and cerebellar activity, as well as provide a platform to help identify and test molecular targets for intervention.