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Molecular Genetics of Scrapie Pathogenesis

National Institute of Allergy and Infectious Disease
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Transmissible spongiform encephalopathies (TSEs or prion diseases) are a group of rare neurodegenerative diseases which include Creutzfeldt-Jakob disease (CJD) in humans, scrapie in sheep, bovine spongiform encephalopathy (BSE) and chronic wasting disease (CWD) in mule deer and elk. TSE infectivity can cross species barriers. The fact that BSE has infected humans in Great Britain and concerns that CWD may act similarly in the US underscores the importance of understanding TSE pathogenesis and developing effective therapeutics. The infectious agent of TSE diseases is called a prion and is largely composed of an abnormally refolded, protease resistant form (PrPSc) of the normal, protease-sensitive prion protein, PrPC. Susceptibility to infection can be influenced by amino acid homology between PrPC and PrPSc while differences in structure between PrPSc molecules are believed to encode strain phenotypes. My laboratory addresses many different aspects of prion diseases at both the molecular and pathogenic level. In particular, my studies focus on: 1) identifying the earliest events which occur during prion infection, 2) defining the molecular pathways involved in prion-associated neurodegeneration, 3) determining the molecular basis of prion strains, 4) determining how PrPC sequence influences PrPSc formation and disease phenotype and, 5) development of effective prion therapeutics. Sporadic Creutzfeldt-Jakob disease (sCJD) is the most prevalent of the human prion diseases. The origin of sCJD is unknown, although the initiating event is thought to be the stochastic misfolding of endogenous PrPC into infectious PrPSc. By contrast, iatrogenic CJD (iCJD) is associated with exposure to an exogenous source of PrPSc. In both sCJD and iCJD, heterozygosity at residue 129 for methionine (M) or valine (V) in the prion protein gene may affect disease phenotype, onset and progression. However, the relative contribution of each PrPC allotype to PrPSc in heterozygous cases of CJD is unknown. In 2015, we completed mass spectrometry studies demonstrating that the relative abundance of PrPSc with M or V at residue 129 was highly variable in MV cases of sCJD but dominated by PrPSc with a valine at residue 129 in cases of MV iCJD. Surprisingly, the PrPSc allotype ratio had no correlation with CJD type, age at clinical onset, or disease duration. Mechanistically, our data are consistent with the origin of sCJD being the random misfolding of PrPC of either allotype into PrPSc and the origin of iCJD being exposure to a limited source of PrPSc. Our study represents the first significant attempt to understand the influence of PrPSc allotype in CJD pathogenesis. A revised manuscript is currently under final review at the high impact journal ACTA Neuropathologica. In 2015, we continued in vivo work to look at early events during prion infection following intracranial inoculation. These studies are designed to provide critical information about the events that occur during the first few hours following exposure to prions, including when formation of new PrPSc occurs and how PrPC is affected. Our most recent data have shown that the cellular location and biochemical properties of the host PrPC molecule change substantially during the first few hours post-infection. A manuscript describing these results is in preparation. Although there is an increasing body of work suggesting that mitochondrial dysfunction plays a role in several neurodegenerative diseases, the role of mitochondria in prion pathogenesis is poorly understood. In a paper we recently published that is described in our 2014 Annual Report J. Proteome Res. 13: 4620-4634 (2014), our proteomic analysis of two different mouse prion models suggested that mitochondrial pathways of apoptosis were involved the neurodegeneration associated with non-amyloid prion disease. In 2015, we have initiated studies looking at how mitochondrial viability and bioenergetics change during the course of disease in multiple different models of murine prion infection. Our studies are the first to look at mitochondrial function throughout the course of prion disease and have the potential to identify new targets for therapeutic intervention. Finally, in 2015 we completed preliminary studies to test whether or not inhibitors of neuroinflammation can also inhibit or delay prion disease. These in vivo studies showed that a strong neuroinflammatory inhibitor had no effect on prion disease progression. In 2015, we also completed a collaboration with Dr. Pamela Skinners lab which demonstrated that treatment with heterologous prion protein, i.e. PrPC with an amino acid sequence different from that of the endogenous host PrPC, can inhibit the progression of prion disease.
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Nat'l. Inst. of Allergy and Infectious Diseases
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Viruses and Prions
Bacterial Pathogens
Prevention and Control
Meat, Poultry, Game