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(American Journal of Pathology. 2001;158:2201-2207.)
© 2001 American Society for Investigative Pathology

Regular Article

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^* and Bernardino Ghetti^*

From the Indiana Alzheimer Disease Center^*
and the Departments of Pathology and Laboratory Medicine,
Medical and Molecular Genetics,
and Neurology,
Indiana University School of Medicine, Indianapolis, Indiana; the Departments of Pathology^¶
and Neurology,^||
University of Washington School of Medicine, Seattle, Washington; the Department of Pathology,^**
Oregon Health Sciences University, Portland, Oregon; the Department of Neurology,
University of Kansas Medical Center, Kansas City, Kansas; and the Istituto Nazionale Neurologico "Carlo Besta",
Milano, Italy

Gerstmann-Sträussler-Scheinker disease (GSS) is characterized by the accumulation of proteinase K (PK)-resistant prion protein fragments (PrP^sc) 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 PrP^sc species in both GSS A117V and F198S. In all GSS A117V patients, the 7-kd PrP^sc 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 PrP^sc 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 PrP^sc fragments of different size and N-terminal sequence, suggests that these mutations generate two distinct PrP conformers.

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