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.
|Bett, Cyrus; Lawrence, Jessica; Kurt, Timothy D et al. (2017) Enhanced neuroinvasion by smaller, soluble prions. Acta Neuropathol Commun 5:32|
|Kurt, Timothy D; Aguilar-Calvo, Patricia; Jiang, Lin et al. (2017) Asparagine and glutamine ladders promote cross-species prion conversion. J Biol Chem :|
|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|
|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|
|Kurt, Timothy D; Sigurdson, Christina J (2016) Cross-species transmission of CWD prions. Prion 10:83-91|
|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|
|Annamalai, Karthikeyan; Gührs, Karl-Heinz; Koehler, Rolf et al. (2016) Polymorphism of Amyloid Fibrils In Vivo. Angew Chem Int Ed Engl 55:4822-5|
|Kurt, Timothy D; Jiang, Lin; Fernández-Borges, Natalia et al. (2015) Human prion protein sequence elements impede cross-species chronic wasting disease transmission. J Clin Invest 125:1485-96|
|Hiramatsu, Nobuhiko; Chiang, Wei-Chieh; Kurt, Timothy D et al. (2015) Multiple Mechanisms of Unfolded Protein Response-Induced Cell Death. Am J Pathol 185:1800-8|
|Kurt, Timothy D; Jiang, Lin; Fernández-Borges, Natalia et al. (2015) Human prion protein sequence elements impede cross-species chronic wasting disease transmission. J Clin Invest 125:2548|
Showing the most recent 10 out of 26 publications