Abstract
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 approximately 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.
Highlights
The molecular signature of prion diseases is a post-translational modification of the prion protein (PrP)1 from a normal cellular isoform (PrPC) to disease-specific species (PrPSc) (1, 2)
We report that PrP-(82–146)wt has high intrinsic ability to form amyloid fibrils indistinguishable from those observed in GSS disease and that the formation of ordered structures having a parallel -sheet organization is dependent upon the integrity of the Cterminal region
The analysis showed that PrP-(82–146)wt readily formed amyloid fibrils, whereas the entirely scrambled peptide, PrP(82–146)scr, did not generate filamentous structures even after
Summary
The molecular signature of prion diseases is a post-translational modification of the prion protein (PrP) from a normal cellular isoform (PrPC) to disease-specific species (PrPSc) (1, 2). PrP amyloidogenesis occurs consistently in genetic forms of disease, such as Gerstmann-Straussler-Scheinker (GSS) disease and PrP cerebral amyloid angiopathy (7, 8), and in the new variant of Creutzfeldt-Jakob disease that is causally linked to bovine spongiform encephalopathy (9, 10). In all these conditions, amyloid fibrils are associated with PrP aggregates that are devoid of the tinctorial and ultrastructural properties of amyloid (11), suggesting that different PrP peptides or protein conformers may trigger fibrillar or non-fibrillar aggregates. A peptide comprising residues [106–126] showed high propensity to adopt stable -sheet secondary structure and to assemble into straight, unbranched amyloid fibrils, similar in ultrastructure to those observed in GSS patients (20–22). We report that PrP-(82–146)wt has high intrinsic ability to form amyloid fibrils indistinguishable from those observed in GSS disease and that the formation of ordered structures having a parallel -sheet organization is dependent upon the integrity of the Cterminal region
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