Structural properties of Gerstmann-Straussler-Scheinker disease amyloid protein

Prion protein (PrP) amyloid formation is a central feature of genetic and acquired forms of prion disease such as Gerstmann-Straussler-Scheinker disease (GSS) and variant Creutzfeldt-Jakob disease. The major component of GSS amyloid is a PrP fragment spanning residues similar to 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-beta-structure. Second derivative of infrared spectra indicated that PrP-( 82 - 146) aggregates are primarily composed of beta-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.