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Proc Natl Acad Sci U S A 2007 Mar 13;104(11):4712-7

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

Piccardo P, Manson JC, King D, Ghetti B, Barron RM

Barron RM (reprint author), Inst Anim Hlth, Neuropathogenesis Unit, Ogston Bldg,W Mains Rd, Edinburgh EH9 3JF, Midlothian Scotland Inst Anim Hlth, Neuropathogenesis Unit, Edinburgh EH9 3JF, Midlothian Scotland US FDA, Ctr Biol Evaluat & Res, Rockville, MD 20852 USA Indiana Univ, Sch Med, Indiana Alzheimer Dis Ctr, Indianapolis, IN 46202 USA Indiana Univ, Sch Med, Div Neuropathol, Indianapolis, IN 46202 USA


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 (PrP(Sc)) 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-Straussler-Scheinker P102L). Both cases had PrP accumulations in the brain, but each had different PrP(Sc) 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.

Category: Journal Article
PubMed ID: #17360589
Includes FDA Authors from Scientific Area(s): Biologics
Entry Created: 2011-10-04 Entry Last Modified: 2012-08-29