Structural Properties of Gerstmann-Sträussler-Scheinker Disease Amyloid Protein

Mario Salmona, Michela Morbin, Tania Massignan, Laura Colombo, Giulia Mazzoleni, Raffaella Capobianco, Luisa Diomede, Florian Thaler, Luca Mollica, Giovanna Musco, Joseph J. Kourie, Orso Bugiani, Deepak Sharma, Hideyo Inouye, Daniel A. Kirschner, Gianluigi Forloni, Fabrizio Tagliavini

Research output: Contribution to journalArticlepeer-review


Prion protein (PrP) amyloid formation is a central feature of genetic and acquired forms of prion disease such as Gerstmann-Sträussler-Scheinker disease (GSS) and variant Creutzfeldt-Jakob disease. The major component of GSS amyloid is a PrP fragment spanning residues ∼82-146. To investigate the determinants of the physicochemical properties of this fragment, we synthesized PrP-(82-146) and variants thereof, including entirely and partially scrambled peptides. PrP-(82-146) readily formed aggregates that were partially resistant to protease digestion. Peptide assemblies consisted of 9.8-nm-diameter fibrils having a parallel cross-β-structure. Second derivative of infrared spectra indicated that PrP-(82-146) aggregates are primarily composed of β-sheet (54%) and turn (24%) which is consistent with their amyloid-like properties. The peptide induced a remarkable increase in plasma membrane microviscosity of primary neurons. Modification of the amino acid sequence 106-126 caused a striking increase in aggregation rate, with formation of large amount of protease-resistant amorphous material and relatively few amyloid fibrils. Alteration of the 127-146 region had even more profound effects, with the inability to generate amyloid fibrils. These data indicate that the intrinsic properties of PrP-(82-146) are dependent upon the integrity of the C-terminal region and account for the massive deposition of PrP amyloid in GSS.

Original languageEnglish
Pages (from-to)48146-48153
Number of pages8
JournalJournal of Biological Chemistry
Issue number48
Publication statusPublished - Nov 28 2003

ASJC Scopus subject areas

  • Biochemistry


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