Most prion strains infect a relatively small number of animal species, but the strain responsible for bovine spongiform encephalopathy (BSE) and variant Creutzfeldt Jakob disease (vCJD) is remarkably promiscuous. The BSE/vCJD strain has caused epidemics in a wide variety of animal species, including humans, but it is unclear how this strain originated and why it is particularly adept at crossing species barriers. Here, we propose to study how promiscuous prion strains originate and identify the molecular mechanism responsible for their ability to cross species barriers easily. We recently reported that cofactor molecules regulate the major strain properties of mammalian prions, including neurotropism and PrPSc conformation. Building upon this critical result, we will now study whether cofactor molecules also play a role in cross- species transmission of prions. Our hypothesis is that prions originally formed with a particular cofactor will be more likely to cross a species barrier if that cofactor is available by modulating the potential folding pathways for PrP molecules. We will also characterize and isolate the cofactor molecule(s) responsible for maintaining the strain properties of the BSE/vCJD strain, including its ability to infect multiple animal species. To do this, we will employ a simple reconstitution assay in which maintenance of the BSE/vCJD strain PrPSc conformation can be monitored rapidly. Finally, we will test the hypothesis that promiscuous prion strains are created from non- promiscuous strains as a result conformational selection during the commercial heat rendering process used to recycle animal carcasses. To test this hypothesis, we will simulate the rendering process in the laboratory and study whether sheep scrapie and deer CWD can be converted into promiscuous strains capable of infecting humans or cows. These studies will have an immediate impact on public health.
Prions are unusual infectious agents that cause fatal brain diseases in humans and animals in our food supply including cows, deer, goats, and sheep. Prion diseases can pass from one animal species to another, and some specific isolates or strains of prions responsible for epidemics such as bovine spongiform encephalopathy (BSE or mad cow disease) appear to be more promiscuous in their ability to cross species barriers than others. In this proposal, we will study how zoonotic strains such as BSE originate and why they cross species barriers so easily. Building upon a series of important discoveries made in our laboratory showing that specific cofactor molecules are required for prion infectivity and strain-specific features, we will study how such cofactor molecules influence the ability of prions to cross species barriers, characterize the cofactor molecules that are responsible for maintaining the strain properties of BSE prions that cause variant Creutzfeldt-Jakob disease (vCJD) in humans. We will also test the idea that promiscuous prion strains arise as a result of the commercial heat rendering process;these experiments aim to recapitulate the origin of the BSE strain, and will provide critical information about the potential risks of rendering other prio strains such as CWD.
|Supattapone, Surachai (2014) Elucidating the role of cofactors in mammalian prion propagation. Prion 8:100-5|
|Zurawel, Ashley A; Walsh, Daniel J; Fortier, Sean M et al. (2014) Prion nucleation site unmasked by transient interaction with phospholipid cofactor. Biochemistry 53:68-76|
|Supattapone, Surachai (2014) Synthesis of high titer infectious prions with cofactor molecules. J Biol Chem 289:19850-4|
|Miller, Michael B; Wang, Daphne W; Wang, Fei et al. (2013) Cofactor molecules induce structural transformation during infectious prion formation. Structure 21:2061-8|
|Walsh, Daniel J; Noble, Geoffrey P; Piro, Justin R et al. (2012) Non-reducing alkaline solubilization and rapid on-column refolding of recombinant prion protein. Prep Biochem Biotechnol 42:77-86|
|Miller, Michael B; Supattapone, Surachai (2011) Superparamagnetic nanoparticle capture of prions for amplification. J Virol 85:2813-7|
|Piro, Justin R; Harris, Brent T; Supattapone, Surachai (2011) In situ photodegradation of incorporated polyanion does not alter prion infectivity. PLoS Pathog 7:e1002001|
|Piro, Justin R; Supattapone, Surachai (2011) Photodegradation illuminates the role of polyanions in prion infectivity. Prion 5:49-51|
|Piro, Justin R; Wang, Fei; Walsh, Daniel J et al. (2011) Seeding specificity and ultrastructural characteristics of infectious recombinant prions. Biochemistry 50:7111-6|
|Miller, Michael B; Geoghegan, James C; Supattapone, Surachai (2011) Dissociation of infectivity from seeding ability in prions with alternate docking mechanism. PLoS Pathog 7:e1002128|
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