Prions are unique, protein-only infectious agents that are responsible for a group of fatal neurodegenerative diseases such as Creutzfeldt-Jakob disease in humans, bovine spongiform encephalopathy in cattle and chronic wasting disease in deer and elk. Human prion diseases are especially poorly understood, largely due to their vast phenotypic heterogeneity that arises from a large spectrum of diverse human prion strains. It is generally accepted that the prion agent multiplies by binding to normal prion protein (PrPC) and converting it into a conformationally distinct pathogenic molecule (PrPSc), but the mechanism of this process remains unclear. A growing number of studies suggest a critical role in prion disease pathogenesis of small, relatively protease sensitive oligomers that appear to control two fundamental steps in the disease pathogenesis: prion replication rate and toxicity. One of the primary objectives of the proposed research is to advance molecular level understanding of the properties of oligomeric PrPSc (oPrPSc) and the mechanism by which these oligomers contribute to the pathogenic process in different phenotypes of sporadic Creutzfeldt-Jakob disease (sCJD). The first Specific Aim is to characterize the structural organization of oPrPSc and define the role of this organization in the replication, propagation and toxicity of the most common strains of sCJD.
The second Aim i s to identify early critical conformational steps in the interaction between PrPC and oPrPSc, the steps that likely play a major role in triggering toxic signaling, creating human prions and controlling prion evolution. If successful, the proposed studies should not only shed new light on the pathogenic mechanism in human prion disorders, but also provide a basis for understanding the relationship between PrPSc structure and strain properties of human prions.

Public Health Relevance

Human prion disease are a group of fatal, neurodegenerative disorders caused by misfolded prion protein. Small and mobile assemblies of prions are the most toxic and potent seeds linked to the development of symptoms and spread of pathology. The proposed studies will deepen our understanding of the molecular basis of these neurodegenerative conditions, their infectiousness, and provide a foundation for the development of novel therapeutic strategies that target prion oligomers .

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
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Wong, May
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Case Western Reserve University
Schools of Medicine
United States
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