Grant: Project Grant

Prion diseases, such as Creutzfeldt-Jakob Disease (CJD) and Bovine Spongiform Encephalopathy (BSE), also known as Mad Cow Disease, are fatal neurodegenerative diseases that afflict humans and animals. This research aims to advance our understanding of these diseases and discover a treatment for them. We know that we could extend prion disease survival if we were able to reduce the levels of a particular protein, the cellular prion protein (PrPC). We also know that it would be safe to do so because individuals whose cells produce half the levels of PrPC are not impacted in their health, and animals who produce no PrPC are similarly unaffected. We recently discovered that PrPC binds to sodium-potassium ATPases (NKAs), specific transport proteins that pump charged potassium and sodium metals in and out of cells. We hypothesized that targeting NKAs with their natural inhibitors, cardiac glycosides (CGs), may cause cells to internalize and degrade NKAs, and that PrPC residing next to NKAs may get co-degraded. In preparation of this proposal, we have validated this idea in several relevant human cell models. We also have developed a synthetic CG that has favorable characteristics for brain applications. The current proposal is informed by these data and will address in independent, yet synergistic, aims the question: Can treatment with CGs reduce the levels of PrPC and extend prion disease survival? The project builds on substantial unpublished data that tie NKAs to prion diseases. In collaboration with an international team, we will reveal in detail the mechanism of action through which CGs reduce PrPC levels and provide proof-of-principle pre-clinical data for the treatment of prion diseases using this novel treatment modality. Moreover, the ability to suppress PrPC levels may translate into a treatment of Alzheimer's disease (AD), because PrPC is widely believed to be a critical player in a cascade of events that leads to the demise of brain cells in AD.