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

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-
Stra¨ussler-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. Al3+ 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.