Transmissible spongiform encephalopathies (TSEs) are a group of neurodegenerative diseases affecting a wide variety of mammals including sheep and goats (scrapie), cervid spp. (chronic wasting disease), and humans (Creutzfeldt-Jakob disease). Our studies are focused on the prion protein (PrP) due to the critical role of this protein in controlling many aspects of TSE pathogenesis such as susceptibility to disease and interspecies transmission. A central event in TSE disease involves the conversion of the normal host cellular prion protein (PrPC) to a partially protease-resistant, aggregated, disease-associated isoform (PrPSc). TSE-induced pathology is usually associated with PrP-res deposition, but the mechanism of neurodegeneration is not understood. The nature of the infectious agent, called a prion, remains uncertain but is thought to be composed primarily of misfolded PrP, perhaps in complex with another host accessory molecule(s). PrPC is a glycosylphosphatidylinositol (GPI)-anchored glycoprotein, and the majority of PrPSc produced in vivo contains this GPI anchor. Membrane association of both normal and disease-associated PrP isoforms may influence many features of prion disease and PrPC function. Our work is focused on elucidating mechanisms of uptake, replication, and spread of prions, in addition to determining the biochemical composition of mammalian prions. In 2013, we have: 1) continued the characterization of novel synthetic strains of TSE agents that originate from purified recombinant PrP;2) further investigated mechanisms of uptake, propagation, and intercellular spread of PrPSc via imaging studies in novel neuronal culture systems;and 3) developed TC-scanning, a new technique for mapping sites of intermolecular interaction.
|Hollister, Jason R; Lee, Kil Sun; Dorward, David W et al. (2015) Efficient uptake and dissemination of scrapie prion protein by astrocytes and fibroblasts from adult hamster brain. PLoS One 10:e0115351|
|Vascellari, Sarah; Orru, Christina D; Hughson, Andrew G et al. (2012) Prion seeding activities of mouse scrapie strains with divergent PrPSc protease sensitivities and amyloid plaque content using RT-QuIC and eQuIC. PLoS One 7:e48969|
|Raymond, Gregory J; Race, Brent; Hollister, Jason R et al. (2012) Isolation of novel synthetic prion strains by amplification in transgenic mice coexpressing wild-type and anchorless prion proteins. J Virol 86:11763-78|
|Smirnovas, Vytautas; Baron, Gerald S; Offerdahl, Danielle K et al. (2011) Structural organization of brain-derived mammalian prions examined by hydrogen-deuterium exchange. Nat Struct Mol Biol 18:504-6|
|Taguchi, Yuzuru; Shi, Zhen-Dan; Ruddy, Brian et al. (2009) Specific biarsenical labeling of cell surface proteins allows fluorescent- and biotin-tagging of amyloid precursor protein and prion proteins. Mol Biol Cell 20:233-44|
|Caughey, Byron; Baron, Gerald S; Chesebro, Bruce et al. (2009) Getting a grip on prions: oligomers, amyloids, and pathological membrane interactions. Annu Rev Biochem 78:177-204|
|Caughey, Byron; Baron, Gerald S (2008) Are cheetahs on the run from prion-like amyloidosis? Proc Natl Acad Sci U S A 105:7113-4|