This Research Project examines new aspects of prion strain diversity which may explain the large phenotypic variations of human prion diseases. Three interrelated specific aims are proposed.
Specific Aim 1 focuses on two novel mechanisms that can contribute to strain and disease phenotype diversity. The first mechanism postulates that the presence of protease-sensitive scrapie prion protein (PrPSc) is a major factor controlling the disease phenotype. The second mechanism is based on the hypothesis that the phenotypic variability is also regulated by preferential formation of distinct PrPSc subtypes in individuals who are heterozygous at codon 129 of the PrP gene. These studies will provide novel explanations for the diversity of human prion diseases and strains.
Specific Aim 2 examines the role of PrP glycosylation in strain characteristics, phenotype determination, and transmissibility. Preliminary data indicate that in contrast to observation on mouse prions, glycan-free human prions replicate more efficiently but reduce phenotypic differences. This research relies on a recently generated line of transgenic mice expressing unglycosylated human PrP.
Specific Aim 3 seeks to elucidate the molecular basis underlying the distinct PrPSc and transmission properties of typical prion diseases such as sporadic Creutzfeldt-Jakob disease (sCJD) and atypical prion diseases such as Gerstmann-Strussler-Scheinker disease (GSS) and the recently discovered variably protease sensitive prionopathy (VPSPr). Specific features have been preliminarily identified in PrPSc, such as the lack of the C-terminal anchor, that point to distinct conformational characteristics associated with low transmissibility. These PrPSc characteristics will be comparatively examined. New data also show that, although VPSPr indeed transmits poorly to Tg mice expressing normally glycosylated human PrPC, transmission of this disease to Tg mice expressing unglycosylated human PrP is strikingly efficient. Transmissibility of GSS subtypes to Tg mice expressing unglycosylated PrP will be attempted. If successful, GSS will be included in a comparative conformational analysis of the native and replicated PrPSc from VPSPr, sCJD and sFI. This Research Project is one of the components of a larger Program Project and involves close interactions with other components of this Program. Project Summary/

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program Projects (P01)
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Special Emphasis Panel (ZAI1-RWM-M (S3))
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Case Western Reserve University
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Notari, Silvio; Appleby, Brian S; Gambetti, Pierluigi (2018) Variably protease-sensitive prionopathy. Handb Clin Neurol 153:175-190
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