Human prion diseases are a diverse group of neurodegenerative disorders that include Creutzfeldt-Jakob disease (CJD), fatal insomnia (familial and sporadic), Gerstmann-Straussler-Scheinker (GSS) disease and variably protease-sensitive prionopathy (VPSPr). Despite large phenotypic variability, a common denominator of all these diseases is the accumulation of proteinase-resistant aggregates of prion protein, PrPSc. While some of these diseases (e.g., CJD) are known to be highly transmissible, transmissibility potential of other members of this group is less well established. The long-term objective of this research is to advance the understanding of the molecular basis, transmissibility properties and phenotypic variability of these disorders. Three interrelated specific aims are proposed.
Specific Aim 1 focuses on transmissibility properties of GSS subtypes and biochemical and conformational features of PrPSc that determine phenotypic variability of these diseases.
This aim i ncludes experiments with PrPSc from GSS brain tissue as well as novel synthetic prions, the transmissibility of which will be studied using new lines of transgenic mice expressing human prion protein.
Specific Aim 2 examines the role of PrP glycosylation in strain characteristics, phenotype determination, and transmissibility. Preliminary data indicate that, in contrast to observations 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 of the recently discovered variably protease sensitive prionopathy (VPSPr). Specific features have been preliminarily identified in PrPSc that point to distinct conformational characteristics associated with this disease and a possible pathogenic mechanism. These PrPSc characteristics will be further examined using a battery of biochemical and conformational assays. Furthermore, new data suggest that, although VPSPr transmits poorly to transgenic mice expressing normally glycosylated human prion protein, transmission of this disease to transgenic mice expressing unglycosylated human PrP might be much more efficient. These transmissibility properties will be further assessed and characterized.

Public Health Relevance

Human prion diseases are a group of neurodegenerative disorders that include many different subtypes. Understanding the mechanism of these diseases and their transmissibility is of fundamental importance for disease diagnosis, clinical practice as well as efforts to develop therapeutic strategies.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
1R01NS083687-01A1
Application #
8769420
Study Section
Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
Program Officer
Wong, May
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Case Western Reserve University
Department
Pathology
Type
Schools of Medicine
DUNS #
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Scott-McKean, Jonah J; Surewicz, Krystyna; Choi, Jin-Kyu et al. (2016) Soluble prion protein and its N-terminal fragment prevent impairment of synaptic plasticity by Aβ oligomers: Implications for novel therapeutic strategy in Alzheimer's disease. Neurobiol Dis 91:124-31
Theint, Theint; Nadaud, Philippe S; Surewicz, Krystyna et al. (2016) (13)C and (15)N chemical shift assignments of mammalian Y145Stop prion protein amyloid fibrils. Biomol NMR Assign :
Choi, Jin-Kyu; Cali, Ignazio; Surewicz, Krystyna et al. (2016) Amyloid fibrils from the N-terminal prion protein fragment are infectious. Proc Natl Acad Sci U S A 113:13851-13856
Pirisinu, Laura; Di Bari, Michele A; D'Agostino, Claudia et al. (2016) Gerstmann-Sträussler-Scheinker disease subtypes efficiently transmit in bank voles as genuine prion diseases. Sci Rep 6:20443
Williams, Thomas L; Choi, Jin-Kyu; Surewicz, Krystyna et al. (2015) Soluble Prion Protein Binds Isolated Low Molecular Weight Amyloid-β Oligomers Causing Cytotoxicity Inhibition. ACS Chem Neurosci 6:1972-80
Orrú, Christina D; Groveman, Bradley R; Raymond, Lynne D et al. (2015) Bank Vole Prion Protein As an Apparently Universal Substrate for RT-QuIC-Based Detection and Discrimination of Prion Strains. PLoS Pathog 11:e1004983
Cali, Ignazio; Miller, Cathleen J; Parisi, Joseph E et al. (2015) Distinct pathological phenotypes of Creutzfeldt-Jakob disease in recipients of prion-contaminated growth hormone. Acta Neuropathol Commun 3:37
Notari, Silvio; Xiao, Xiangzhu; Espinosa, Juan Carlos et al. (2014) Transmission characteristics of variably protease-sensitive prionopathy. Emerg Infect Dis 20:2006-14
Xiao, Xiangzhu; Yuan, Jue; Qing, Liuting et al. (2014) Comparative Study of Prions in Iatrogenic and Sporadic Creutzfeldt-Jakob Disease. J Clin Cell Immunol 5: