The heretical nature of prions and the reported transmission of the disease between animals to humans are important to fully understand key aspects of prion biology, including the biochemical and structural basis of species barrier, strain diversity, and the relationship between prion replication and neurodegeneration. A better understanding of these issues would contribute to prevent the emergence of new diseases with potential for epidemic consequences and to develop much needed therapeutic strategies for these incurable diseases. The main goal of this project is to elucidate the molecular basis of prion strains, their influence on species barrier and the biochemical/structural properties modulating the replication and pathogenicity of prions as well as use of this knowledge to develop a novel therapeutic strategy for prion diseases. The project is structured around several highly innovative hypotheses.
In specific aim 1 we will test the hypothesis that that the animal to human species barrier depends on a complex interaction between the degree of similarity on the PrP primary sequence and the strain characteristics of the infectious agent. For these studies we will focus on the two most prevalent animal prion diseases: scrapie in sheep and CWD in cervids.
In specific aim 2 we will test the hypothesis that the prion strain associated with vCJD in humans consists of an ensemble of PrPSc variants with distinct biochemical properties and that the tissue environment influences prion replication by selecting specific PrPSc conformations from the pool. These studies are inspired on our recent results indicating that the features of PrPSc accumulated in spleen or brain from vCJD patients are different.
In specific aim 3 we propose to utilize the prion principle to generate a """"""""selfreplicating"""""""" therapy for prion diseases by dissociating prion replication from pathogenicity. The plan is to generate PrPSc variants that efficiently replicates, but do not produce disease. This innocuous prion variant could outcompete a pathogenic prion by recruiting and converting the PrPC substrate into more of the therapeutic prion, preventing infectivity. Project Summary/
Transmissble spongiform encephalopathies, or prion diseases, are neurodegenerative disorders that can be transmitted from animals to humans. Understanding the pathogenic process in these disorders and the mechanisms by which they are transmitted within and between species is of fundamental importance for protecting the human population as well for the development of therapeutic strategies.
|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|
|Li, Qiuye; Wang, Fei; Xiao, Xiangzhu et al. (2018) Structural attributes of mammalian prion infectivity: Insights from studies with synthetic prions. J Biol Chem 293:18494-18503|
|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|
|Theint, Theint; Nadaud, Philippe S; Surewicz, Krystyna et al. (2017) 13C and 15N chemical shift assignments of mammalian Y145Stop prion protein amyloid fibrils. Biomol NMR Assign 11:75-80|
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