title: Two alternative pathways for generating transmissible prion disease de novo.
abstract: BACKGROUND
  Previous studies established that prion disease with unique strain-specific phenotypes could be induced by in vitro-formed recombinant PrP (rPrP) fibrils with structures different from that of authentic prions, or PrP(Sc). To explain the etiology of prion diseases, new mechanism proposed that in animals the transition from rPrP fibrils to PrP(Sc) consists of two main steps: the first involves fibril-induced formation of atypical PrPres, a self-replicating but clinically silent state, and the second consists of atypical PrPres-dependent formation of PrP(Sc) via rare deformed templating events.
  
  
  RESULTS
  In the current study, atypical PrPres with characteristics similar to those of brain-derived atypical PrPres was generated in vitro. Upon inoculation into animals, in vitro-generated atypical PrPres gave rise to PrP(Sc) and prion disease with a phenotype similar to those induced by rPrP fibrils. Significant differences in the sialylation pattern between atypical PrPres and PrP(Sc) suggested that only a small sub-fraction of the PrP(C) that is acceptable as a substrate for PrP(Sc) could be also recruited by atypical PrPres. This can explain why atypical PrPres replicates slower than PrP(Sc) and why PrP(Sc) outcompetes atypical PrPres.
  
  
  CONCLUSIONS
  This study illustrates that transmissible prion diseases with very similar disease phenotypes could be produced via two alternative procedures: direct inoculation of recombinant PrP amyloid fibrils or in vitro-produced atypical PrPres. Moreover, this work showed that preparations of atypical PrPres free of PrP(Sc) can give rise to transmissible diseases in wild type animals and that atypical PrPres generated in vitro is an adequate model for brain-derived atypical PrPres.
authors.affiliation: Center for Biomedical Engineering and Technology, University of Maryland School of Medicine, 111 S. Penn St., Baltimore, MD, 21201, USA. NMakarava@umaryland.edu.|Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD, USA. NMakarava@umaryland.edu.
authors.forename: Natallia
authors.initials: N
authors.lastname: Makarava
authors.affiliation: Center for Biomedical Engineering and Technology, University of Maryland School of Medicine, 111 S. Penn St., Baltimore, MD, 21201, USA. rsavtchenko@yahoo.com.|Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD, USA. rsavtchenko@yahoo.com.
authors.forename: Regina
authors.initials: R
authors.lastname: Savtchenko
authors.affiliation: Center for Biomedical Engineering and Technology, University of Maryland School of Medicine, 111 S. Penn St., Baltimore, MD, 21201, USA. Baskakov@umaryland.edu.|Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD, USA. Baskakov@umaryland.edu.
authors.forename: Ilia V
authors.initials: IV
authors.lastname: Baskakov
mesh_terms: D000682:Amyloid / Q000008:administration & dosage / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D006224:Cricetinae; D004195:Disease Models, Animal; D010641:Phenotype; D017096:Prion Diseases / Q000209:etiology* / Q000473:pathology / Q000635:transmission*; D011328:Prions / Q000235:genetics / Q000378:metabolism*; D017510:Protein Folding; D011994:Recombinant Proteins / Q000378:metabolism
chemical_list: D000682:Amyloid; D011328:Prions; D011994:Recombinant Proteins