Disease Transmission and Species Barrier Anne Busch

Transmission of Prion diseases Infectious prion disease spread through: Ingestion of diseased tissue or body fluid Inhalation of aerosols (in mice) Transmission: donor prion enters the recipient cell → host prion binds to the ends of amyloid prion (template) → host prion adopts amyloid form 2

The Species Barrier Pathogenic material from one species may not cause disease in another species High species barrier – inefficient transmission May be overcome by prolonged incubation that results in selection of 'mutant' prion Determined by 1. primary structure of PrP gene 2. specific prion variant No documented cases of humans contracting prion disease from sheep scrapie, but bovine scrapie is able to infect humans. 3

PrP sequence homology Higher degree of conservation → easier transmission Conclusively shown by transgenic mice studies Knockout & transgenic mice Prion protein must be present in the cell Most efficient for the same species 4

Prion species variants These differences are retained after several passages 5

Prion species Strain-specific properties correlate with conformational differences which may be due to: differences in tertiary structure quaternary assemblies of the same fold differences in primary structure not required for different strains covalent modifications like N-linked glycosalation 7

Prolonged Incubation can overcome the species barrier Prion variant generation by cross-seeding could overcome species barriers to prion transmission. (a) An altered form (a 'mutant') of mouse scrapie strain 139A is selected by the high species barrier encountered when it is transferred to hamsters - 8

Prolonged Incubation can overcome the species barrier (c) Schematic diagram showing partial templating by species A amyloid filament of species B protein. Species B protein sequence is incompatible with all of species A filament structure, and so assumes an altered self-propagating form – a prion variant. This is responsible for the new variant vCJD outbreak in 1996 thought to be due

Questions? Kimberlin RH, Cole S, Walker CA: Temporary and permanent modifications to a single strain of mouse scrapie on transmission to rats and hamsters. J Gen Virol 1987, 68:1875-1881 Collinge J, Clarke AR: A general model of prion strains and their pathogenicity. Science 2007, 318:930-936.

References Diego Kaski, Prion Diseases, Medicine 37:11, 2009 Wen-Quan Zou, Modeling of human prions and prion diseases in vitro and in vivo, Vol. I, No. 2, 2004 Masato Enari, Scrapie prion protein accumulation by scrapie- infected neuroblastomacells abrogated by exposure to a prion protein antibody, PNAS, 9295-9299, 2001 Rodrigo Morales, The prion strain phenomenon: Molecular basis and unprecedented features, BBA, 681-691, 2007 Jisuk Yun, The first report of RPSA polymorphisms, also called 37/67kDa LRP/LR gene, in sporadic Creutzfeldt-Jakob disease (CJD). Kimberlin RH, Cole S, Walker CA: Temporary and permanent modifications to a single strain of mouse scrapie on transmission to rats and hamsters. J Gen Virol 1987, 68:1875-1881 Collinge J, Clarke AR: A general model of prion strains and their pathogenicity. Science 2007, 318:930-936.