Title: Molecular Insights into Ferroptosis as a Therapeutic Target for Huntington’s Disease
Description: Ferroptosis is a non-apoptotic, regulated form of cell death that is characterized by the iron-dependent lethal accumulation of lipid peroxides and lipid peroxide byproducts. Huntington’s disease (HD) is an autosomal neurodegenerative disease with characteristic motor, psychiatric, and cognitive signs and symptoms caused by the expansion of CAG repeats in the Huntingtin gene, resulting in the production of pathogenic protein with an extended polyglutamine tract that is prone to aggregation. Accumulating evidence has identified links between ferroptosis and HD suggesting that ferroptosis inhibition may provide therapeutic benefit. However, the ability to evaluate this potential has been limited by the unavailability of potent, brain-penetrant specific ferroptosis inhibitors. This dissertation evaluates two different types of ferroptosis inhibitors and increases the available molecular tools to investigate the role of ferroptosis in the etiology of HD. In the second and third chapters, two new classes of ferrostatin analogs, termed fourth and fifth generation ferrostatins, are developed and their in vitro and in vivo properties characterized.

These efforts identify three, fifth generation analogs that are potent, brain-penetrant, and stable and can be administered chronically to symptomatic HD mice. The fourth chapter provides molecular insights into the mechanism of action of the hypocholesterolemic drug probucol in inhibiting ferroptosis and identifies cellular cholesterol levels and cholesterol import as regulators of ferroptosis. In sum, this work provides new molecular tools and insights that can be utilized to elucidate the contribution of ferroptosis to HD and other disease states.