Grant: Project Grant

Prion disorders are diseases of the ageing brain that affect both humans and animals. Examples include Creutzfeldt-Jakob disease in humans, scrapie in sheep, chronic wasting disease in deer/elk, and "mad cow disease". In prion disease, a protein (the "prion protein") clumps together in the brain to form aggregates called prions. While protein aggregates also feature in other neurodegenerative disorders such as Alzheimer's and Parkinson's disease, prions are unique in that they can be infectious, transmitting disease between people or animals under certain circumstances. However, most cases of prion disease in humans do not result from an infection but instead occur due to a rare occurrence in which prions form spontaneously in the brain. This is thought to be the event that initiates the sporadic (spontaneous) and genetic prion diseases. Yet, little is known about how and why the prion protein sometimes clumps together to form prions. Understanding how prions form is likely to be crucial for the development of effective therapies, especially for those at risk of developing a genetic prion disease. Previously, we developed genetically engineered mice that spontaneously form prions in their brains as they age. These mice, which exhibit all the hallmarks of prion disease, produce the prion protein from the bank vole, a rodent that displays a remarkably enhanced susceptibility to prions. The goal of this proposal is to utilize these mice to understand the sequence of events that occur in the brain during spontaneous prion formation. These studies will identify new strategies for treating prion diseases, for which no cures or treatments currently exist. Moreover, because the formation of protein clumps that can spread within the brain also happens in Alzheimer's and Parkinson's disease, our proposed work will shed light into the earliest, and perhaps treatable, events that occur in more common neurodegenerative disorders.