Prion diseases are transmissible fatal
neurodegenerative disorders affecting humans and other mammals. The disease transmission can occur between different species but is limited by the sequence homology between host and inoculum. The crucial molecular event in the progression of this disease is
prion formation, starting from the conformational conversion of the normal, membrane-anchored
prion protein (PrPC) into the misfolded, β-sheet-rich and aggregation-prone
isoform (PrPSc), which then self-associates into the infectious
amyloid form called
prion.
Amyloid is the aggregate formed from one-dimensional
protein association. As
amyloid formation is a key hallmark in
prion pathogenesis, studying which segments in
prion protein are involved in the
amyloid formation can provide molecular details in the cross-species transmission barrier of
prion diseases. However, due to the difficulties of studying
protein aggregates, very limited knowledge about
prion structure or
prion formation was disclosed by now. In this study, cross-seeding assay was used to identify the segments involved in the
amyloid fibril formation of full-length hamster
prion protein, SHaPrP(23-231). Our results showed that the residues in the segments 108-127, 172-194 (helix 2 in PrPC) and 200-227 (helix 3 in PrPC) are in the
amyloid core of hamster
prion fibrils. The segment 127-143, but not 107-126 (which corresponds to hamster sequence 108-127), was previously reported to be involved in the
amyloid core of full-length mouse
prion fibrils. Our results indicate that hamster
prion protein and mouse
prion protein use different segments to form the
amyloid core in amyloidogenesis. The sequence-dependent core formation can be used to explain the seeding barrier between mouse and hamster.