The long-term objective of this research is to understand molecular aspects of the pathogenic process in prion diseases. These transmissible neurodegenerative disorders include Creutzfeldt-Jakob disease in humans, bovine spongiform encephalopathy in cattle and chronic wasting disease in cervids. The most intriguing aspect of prion diseases is the nature of the infectious agent that is composed of a misfolded form of the prion protein, PrPSc. This misfolded conformer is believed to self-replicate by the mechanism involving binding to the normal prion protein, PrPC, and forcing its conformational conversion to the sheet- rich PrPSc state. However, the mechanism of the PrPC ? PrPSc conversion and, especially, the structural aspects of this process remain poorly understood. The lack of information in this regard represents a critical gap in prion research, hindering efforts to understand the molecular basis of TSE diseases as well as development of effective strategies for pharmacological intervention. The overall goal of this Project is to gain insight into the structural basis of prion protein conversion and, especially, the structure of PrPSc conformer. The first specific aim seeks to gain insight into the molecular and structural basis of seeded conversion of prion protein to the infectious form, with the working hypothesis that the key initial event in this reaction is a conformational transition within a relatively short segment of the protein, from which ?-structure propagates into the surrounding regions.
The second aim takes advantage of the recent seminal finding that highly infectious prions can be generated in vitro from the recombinant PrP in the presence of additional cofactors. We will use a battery of biophysical techniques to characterize these infectious protein aggregates at all levels of structural organization.
The third aim seeks to determine conformational correlates of transmissibility and phenotypic variability of human prion diseases. This Research Project is one of the components of a larger Program Project. It relies on services provided by the Animal and Neuropathology Cores and involves close scientific interaction with two other Research Projects of this Program.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
1P01AI106705-01A1
Application #
8779061
Study Section
Special Emphasis Panel (ZAI1-RWM-M (S3))
Project Start
Project End
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
1
Fiscal Year
2014
Total Cost
$371,251
Indirect Cost
$96,534
Name
Case Western Reserve University
Department
Type
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
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Aucoin, Darryl; Xia, Yongjie; Theint, Theint et al. (2018) Protein-solvent interfaces in human Y145Stop prion protein amyloid fibrils probed by paramagnetic solid-state NMR spectroscopy. J Struct Biol :
Shannon, Matthew D; Theint, Theint; Mukhopadhyay, Dwaipayan et al. (2018) Conformational Dynamics in the Core of Human Y145Stop Prion Protein Amyloid Probed by Relaxation Dispersion NMR. Chemphyschem :
Kim, Chae; Xiao, Xiangzhu; Chen, Shugui et al. (2018) Artificial strain of human prions created in vitro. Nat Commun 9:2166
Notari, Silvio; Appleby, Brian S; Gambetti, Pierluigi (2018) Variably protease-sensitive prionopathy. Handb Clin Neurol 153:175-190
Diaz-Espinoza, R; Morales, R; Concha-Marambio, L et al. (2018) Treatment with a non-toxic, self-replicating anti-prion delays or prevents prion disease in vivo. Mol Psychiatry 23:777-788
Cali, Ignazio; Cohen, Mark L; Haik, Stephane et al. (2018) Iatrogenic Creutzfeldt-Jakob disease with Amyloid-? pathology: an international study. Acta Neuropathol Commun 6:5
Theint, Theint; Xia, Yongjie; Nadaud, Philippe S et al. (2018) Structural Studies of Amyloid Fibrils by Paramagnetic Solid-State Nuclear Magnetic Resonance Spectroscopy. J Am Chem Soc 140:13161-13166
Cracco, Laura; Appleby, Brian S; Gambetti, Pierluigi (2018) Fatal familial insomnia and sporadic fatal insomnia. Handb Clin Neurol 153:271-299
Theint, Theint; Nadaud, Philippe S; Aucoin, Darryl et al. (2017) Species-dependent structural polymorphism of Y145Stop prion protein amyloid revealed by solid-state NMR spectroscopy. Nat Commun 8:753

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