Aggregation/fibrillogenesis of recombinant human prion protein and Gerstmann-Sträussler-Scheinker disease peptides in the presence of metal ions

Fernanda Ricchelli, Raffaella Buggio, Denise Drago, Mario Salmona, Gianluigi Forloni, Alessandro Negro, Giuseppe Tognon, Paolo Zatta

Research output: Contribution to journalArticlepeer-review


In this study we investigated the role of Cu2+, Mn2+, Zn2+, and Al3+ in inducing defective conformational rearrangements of the recombinant human prion protein (hPrP), which trigger aggregation and fibrillogenesis. The research was extended to the fragment of hPrP spanning residues 82-146, which was identified as a major component of the amyloid deposits in the brain of patients affected by Gerstmann-Sträussler- Scheinker (GSS) disease. Variants of the 82-146 wild-type subunit [PrP-(82-146)wt] were also examined, including entirely, [PrP-(82-146)scr], and partially scrambled, [PrP-(82-146) 106-126scr] and [PrP-(82-146)127-146scr] peptides. Al 3+ strongly stimulated the conversion of native hPrP into the altered conformation, and its potency in inducing aggregation was very high. Despite a lower rate and extent of prion protein conversion into altered isoforms, however, Zn2+ was more efficient than Al3+ in promoting organization of hPrP aggregates into well-structured, amyloid-like fibrillar filaments, whereas Mn2+ delayed and Cu2+ prevented the process. GSS peptides underwent the fibrillogenesis process much faster than the full-length protein. The intrinsic ability of PrP-(82-146)wt to form fibrillar aggregates was exalted in the presence of Zn2+ and, to a lesser extent, of Al3+, whereas Cu2+ and Mn2+ inhibited the conversion of the peptide into amyloid fibrils. Amino acid substitution in the neurotoxic core (sequence 106-126) of the 82-146 fragment reduced its amyloidogenic potential. In this case, the stimulatory effect of Zn2+ was lower as compared to the wild-type peptide; on the contrary Al3+ and Mn2+ induced a higher propensity to fibrillation, which was ascribed to different binding modalities to GSS peptides. In all cases, alteration of the 127-146 sequence strongly inhibited the fibrillogenesis process, thus suggesting that integrity of the C-terminal region was essential both to confer amyloidogenic properties on GSS peptides and to activate the stimulatory potential of the metal ions.

Original languageEnglish
Pages (from-to)6724-6732
Number of pages9
Issue number21
Publication statusPublished - May 30 2006

ASJC Scopus subject areas

  • Biochemistry


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