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Generation of novel neuroinvasive prions following intravenous challenge
Univ Calif San Diego, CA 92093 USA; Univ Calif San Diego, CA 92093 USA.
Univ Calif San Diego, CA 92093 USA; Univ Calif San Diego, CA 92093 USA.
Univ Calif San Diego, CA 92093 USA; Univ Calif San Diego, CA 92093 USA.
Univ Calif San Diego, CA 92093 USA; Univ Calif San Diego, CA 92093 USA.
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2018 (English)In: Brain Pathology, ISSN 1015-6305, E-ISSN 1750-3639, Vol. 28, no 6, p. 999-1011Article in journal (Refereed) Published
Abstract [en]

Prions typically spread into the central nervous system (CNS), likely via peripheral nerves. Yet prion conformers differ in their capacity to penetrate the CNS; certain fibrillar prions replicate persistently in lymphoid tissues with no CNS entry, leading to chronic silent carriers. Subclinical carriers of variant Creutzfeldt-Jakob (vCJD) prions in the United Kingdom have been estimated at 1:2000, and vCJD prions have been transmitted through blood transfusion, however, the circulating prion conformers that neuroinvade remain unclear. Here we investigate how prion conformation impacts brain entry of transfused prions by challenging mice intravenously to subfibrillar and fibrillar strains. We show that most strains infiltrated the brain and caused terminal disease, however, the fibrillar prions showed reduced CNS entry in a strain-dependent manner. Strikingly, the highly fibrillar mCWD prion strain replicated in the spleen and emerged in the brain as a novel strain, indicating that a new neuroinvasive prion had been generated from a previously non-neuroinvasive strain. The new strain showed altered plaque morphology, brain regions targeted and biochemical properties and these properties were maintained upon intracerebral passage. Intracerebral passage of prion-infected spleen re-created the new strain. Splenic prions resembled the new strain biochemically and intracerebral passage of prion-infected spleen re-created the new strain, collectively suggesting splenic prion replication as a potential source. Taken together, these results indicate that intravenous exposure to prion-contaminated blood or blood products may generate novel neuroinvasive prion conformers and disease phenotypes, potentially arising from prion replication in non-neural tissues or from conformer selection.

Place, publisher, year, edition, pages
WILEY , 2018. Vol. 28, no 6, p. 999-1011
Keywords [en]
amyloid; blood; neurodegeneration; protein misfolding; prion disease; strain mutation; transmission
National Category
Neurosciences
Identifiers
URN: urn:nbn:se:liu:diva-154741DOI: 10.1111/bpa.12598ISI: 000457460300016PubMedID: 29505163OAI: oai:DiVA.org:liu-154741DiVA, id: diva2:1291999
Note

Funding Agencies|National Institutes of Health [NS069566, NS076896]; Ramon Areces Foundation; Swedish Research Council [2015-04521, 2015-05868]; Goran Gustafsson Foundation

Available from: 2019-02-26 Created: 2019-02-26 Last updated: 2019-02-26

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