Accumulation of prion protein in the brain that is not associated with transmissible disease

Pedro Piccardo, Jean C. Manson, Declan King, Bernardino Ghetti, Rona M. Barron

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146 Scopus citations

Abstract

Prion diseases or transmissible spongiform encephalopathies are characterized histopathologically by the accumulation of prion protein (PrP) ranging from diffuse deposits to amyloid plaques. Moreover, pathologic PrP isoforms (PrPSc) are detected by immunoblot analysis and used both as diagnostic markers of disease and as indicators of the presence of infectivity in tissues. It is not known which forms of PrP are associated with infectivity. To address this question, we performed bioassays using human brain extracts from two cases with phenotypically distinct forms of familial prion disease (Gerstmann-Sträussler-Scheinker P102L). Both cases had PrP accumulations in the brain, but each had different PrPSc isoforms. Only one of the brains had spongiform degeneration. Tissue from this case transmitted disease efficiently to transgenic mice (Tg PrP101LL), resulting in spongiform encephalopathy. In contrast, inoculation of tissue from the case with no spongiform degeneration resulted in almost complete absence of disease transmission but elicited striking PrP-amyloid deposition in several recipient mouse brains. Brains of these mice failed to transmit any neurological disease on passage, but PrP-amyloid deposition was again observed in the brains of recipient mice. These data suggest the possible isolation of an infectious agent that promotes PrP amyloidogenesis in the absence of a spongiform encephalopathy. Alternatively, the infectious agent may be rendered nonpathogenic by sequestration in amyloid plaques, or PrP amyloid can seed amyloid accumulation in the brain, causing a proteinopathy that is unrelated to prion disease. Formation of PrP amyloid may therefore not necessarily be a reliable marker of transmissible spongiform encephalopathy infectivity.

Original languageEnglish (US)
Pages (from-to)4712-4717
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume104
Issue number11
DOIs
StatePublished - Mar 13 2007

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Keywords

  • Amyloid
  • Gerstmann-Straussler-Scheinker
  • Neurodegeneration
  • Transmissible spongiform encephalopathy

ASJC Scopus subject areas

  • Genetics
  • General

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