Prion diseases are infectious and fatal neurodegenerative disorders with no available treatment. Zoonotic prion transmission is of concern, as the bovine spongiform encephalopathy (BSE) epidemic has led to nearly 200 cases of prion infection in humans. New prion diseases have recently emerged in food animals and wild deer with unknown potential for spread to humans. The molecular mechanisms that underlie prion aggregation, transmission between species, and the prion strains are still poorly understood. Our long term goal is to identify the key residues of the prion protein that govern species barriers and strain conformation. The 2-a2 loop of the prion protein (amino acids 165-175) is a site of exceptionally high sequence variability. Microcrystallography has shown that adjacent 2-a2 loops can align as -sheets with side chains that intermesh in a dry interface as part of the amyloid core. We have shown that two amino acid substitutions in the 2-a2 loop of the mouse prion protein lead to de novo prion disease in transgenic mice. In preliminary studies, these substitutions markedly change the interspecies transmission barriers in mice. Here we propose that the 2-a2 loop also plays an important role for prion transmission to humans and cattle. In this proposal, we will evaluate the impact of the 2-a2 loop residues on prion aggregation, species barriers, and strains.
In Aim 1, we will determine the role of critical residues for prion aggregation and conformational conversion in vitro and in vivo.
In Aim 2, we will assess the importance of the 2-a2 loop region for prion infection of humans and cattle using mouse models that differ only at the loop. Results from these studies will contribute to our understanding of the fundamental mechanisms of prion protein aggregation, aid in our risk assessment of prion transmission to humans, as well as advance the rational design of therapeutics to block prion aggregation.
Prion infections have the potential to spread from animals to humans and have caused deaths as well as enormous economic losses in the UK. Chronic wasting disease (CWD) is an emerging prion disease in deer and elk, transmitted at a rate unparalleled by any other prion disease, and thus may present a risk of infecting humans, our food animals, and other wildlife. We propose to investigate the underlying mechanisms for when and how prions can infect a new host.
| Aguilar-Calvo, Patricia; Bett, Cyrus; Sevillano, Alejandro M et al. (2018) Generation of novel neuroinvasive prions following intravenous challenge. Brain Pathol 28:999-1011 |
| Orrù, Christina D; Soldau, Katrin; Cordano, Christian et al. (2018) Prion Seeds Distribute throughout the Eyes of Sporadic Creutzfeldt-Jakob Disease Patients. MBio 9: |
| Aguilar-Calvo, Patricia; Xiao, Xiangzhu; Bett, Cyrus et al. (2017) Post-translational modifications in PrP expand the conformational diversity of prions in vivo. Sci Rep 7:43295 |
| Bett, Cyrus; Lawrence, Jessica; Kurt, Timothy D et al. (2017) Enhanced neuroinvasion by smaller, soluble prions. Acta Neuropathol Commun 5:32 |
| Sikorska, Beata; Gajos, Agata; Bogucki, Andrzej et al. (2017) Electron microscopic and confocal laser microscopy analysis of amyloid plaques in chronic wasting disease transmitted to transgenic mice. Prion 11:431-439 |
| Kurt, Timothy D; Aguilar-Calvo, Patricia; Jiang, Lin et al. (2017) Asparagine and glutamine ladders promote cross-species prion conversion. J Biol Chem 292:19076-19086 |
| Klionsky, Daniel J (see original citation for additional authors) (2016) Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy 12:1-222 |
| Keene, C Dirk; Darvas, Martin; Kraemer, Brian et al. (2016) Neuropathological assessment and validation of mouse models for Alzheimer's disease: applying NIA-AA guidelines. Pathobiol Aging Age Relat Dis 6:32397 |
| Kurt, Timothy D; Sigurdson, Christina J (2016) Cross-species transmission of CWD prions. Prion 10:83-91 |
| Annamalai, Karthikeyan; Gührs, Karl-Heinz; Koehler, Rolf et al. (2016) Polymorphism of Amyloid Fibrils In Vivo. Angew Chem Int Ed Engl 55:4822-5 |
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