Prion proteins with different conformations accumulate in Gerstmann-Sträussler-Scheinker disease caused by A117V and F198S mutations

Pedro Piccardo, Juris J. Liepnieks, Albert William, Stephen R. Dlouhy, Martin R. Farlow, Katherine Young, David Nochlin, Thomas D. Bird, Randal R. Nixon, Melvyn J. Ball, Charles DeCarli, Orso Bugiani, Fabrizio Tagliavini, Merrill D. Benson, Bernardino Ghetti

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64 Scopus citations

Abstract

Gerstmann-Sträussler-Scheinker disease (GSS) is characterized by the accumulation of proteinase K (PK)-resistant prion protein fragments (PrPsc) of ∼7 to 15 kd in the brain. Purified GSS amyloid is composed primarily of ∼7-kd PrP peptides, whose N terminus corresponds to residues W81 and G88 to G90 in patients with the A117V mutation and to residue W81 in patients with the F198S mutation. The aim of this study was to characterize PrP in brain extracts, microsomal preparations, and purified fractions from A117V patients and to determine the N terminus of PrPsc species in both GSS A117V and F198S. In all GSS A117V patients, the ∼7-kd PrPsc fragment isolated from nondigested and PK-digested samples had the major N terminus at residue G88 and G90, respectively. Conversely, in all patients with GSS F198S, an ∼8-kd PrPsc fragment was isolated having the major N terminus start at residue G74. It is possible that a further degradation of this fragment generates the amyloid subunit starting at W81. The finding that patients with GSS A117V and F198S accumulate PrPsc fragments of different size and N-terminal sequence, suggests that these mutations generate two distinct PrP conformers.

Original languageEnglish (US)
Pages (from-to)2201-2207
Number of pages7
JournalAmerican Journal of Pathology
Volume158
Issue number6
DOIs
StatePublished - Jan 1 2001

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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    Piccardo, P., Liepnieks, J. J., William, A., Dlouhy, S. R., Farlow, M. R., Young, K., Nochlin, D., Bird, T. D., Nixon, R. R., Ball, M. J., DeCarli, C., Bugiani, O., Tagliavini, F., Benson, M. D., & Ghetti, B. (2001). Prion proteins with different conformations accumulate in Gerstmann-Sträussler-Scheinker disease caused by A117V and F198S mutations. American Journal of Pathology, 158(6), 2201-2207. https://doi.org/10.1016/S0002-9440(10)64692-5