Structures and Activities of Prions and Prion Proteins

Caughey, Byron

Abstract

Accomplishments for FY2010: 1) We have extended our experimental support for the conclusion that mammalian prions that cause a transmissible spongiform encephalopathy (TSE or prion disease) can be generated solely from bacterially expressed recombinant prion protein. This discovery provides the most compelling evidence so far for the potential protein-only prion hypothesis for the nature of the TSE infectious agent. However, the data leave open the likelihood that other molecules strongly enhance the infectious titers of pathological forms of prion protein. 2) We have studied the strain-dependent structures of prion seeded recombinant PrP fibrils. 3) We have extended our characterization of TSE strain-dependent differences in the interactions between prion protein and complement factors. 4) We have probed the effects of glycosylation and GPI-anchoring on the conformations of different strains of scrapie-prion protein by infrared spectroscopy. 5) We have studied cellular effects of nucleic acid binding to normal prion protein.

Funding Agency

• Agency: National Institute of Health (NIH)
• Institute: National Institute of Allergy and Infectious Diseases (NIAID)
• Type: Investigator-Initiated Intramural Research Projects (ZIA)
• Project #: 1ZIAAI000580-21
• Application #: 8156862
• Support Year: 21
• Fiscal Year: 2010
• Total Cost: $1,475,196

Institution

• Name: National Institute of Allergy and Infectious Diseases

Publications

Groveman, Bradley R; Raymond, Gregory J; Campbell, Katrina J et al. (2017) Role of the central lysine cluster and scrapie templating in the transmissibility of synthetic prion protein aggregates. PLoS Pathog 13:e1006623

Kraus, Allison; Raymond, Gregory J; Race, Brent et al. (2017) PrP P102L and Nearby Lysine Mutations Promote Spontaneous In Vitro Formation of Transmissible Prions. J Virol 91:

Cracco, Laura; Notari, Silvio; Cali, Ignazio et al. (2017) Novel strain properties distinguishing sporadic prion diseases sharing prion protein genotype and prion type. Sci Rep 7:38280

Wang, Fei; Wang, Xinhe; Orrú, Christina D et al. (2017) Self-propagating, protease-resistant, recombinant prion protein conformers with or without in vivo pathogenicity. PLoS Pathog 13:e1006491

Bett, Cyrus; Lawrence, Jessica; Kurt, Timothy D et al. (2017) Enhanced neuroinvasion by smaller, soluble prions. Acta Neuropathol Commun 5:32

Hughson, Andrew G; Race, Brent; Kraus, Allison et al. (2016) Inactivation of Prions and Amyloid Seeds with Hypochlorous Acid. PLoS Pathog 12:e1005914

Alibhai, James; Blanco, Richard A; Barria, Marcelo A et al. (2016) Distribution of Misfolded Prion Protein Seeding Activity Alone Does Not Predict Regions of Neurodegeneration. PLoS Biol 14:e1002579

Saijo, Eri; Hughson, Andrew G; Raymond, Gregory J et al. (2016) PrPSc-Specific Antibody Reveals C-Terminal Conformational Differences between Prion Strains. J Virol 90:4905-13

Kraus, Allison; Anson, Kelsie J; Raymond, Lynne D et al. (2015) Prion Protein Prolines 102 and 105 and the Surrounding Lysine Cluster Impede Amyloid Formation. J Biol Chem 290:21510-22

Groveman, Bradley R; Kraus, Allison; Raymond, Lynne D et al. (2015) Charge neutralization of the central lysine cluster in prion protein (PrP) promotes PrP(Sc)-like folding of recombinant PrP amyloids. J Biol Chem 290:1119-28