Influence of mutations associated with familial prion-related encephalopathies on biological activity of prion protein peptides

In transmissible spongiform encephalopathies (TSEs), an altered form of pri on protein (PrP), PrPres, aggregates in amyloid fibrils and accumulates in the brain. Several point mutations of the PrP gene have been associated wit h the TSEs, so, to investigate how the mutations affect the biological acti vity of PrP, we analyzed the biological effects and chemicophysical charact eristics of the peptide homologous to the wild-type and mutated sequence of PrP fragments. The mutation P102L altered the biological activity of PrP 8 9-106, which became neurotoxic without changing its fibrillogenic capacity. The mutation (D178N) in the PrP 169-185 strongly increased the neurotoxic activity of the native sequence. In this case, there was also a clear alter ation of the structural conformation. None of the other mutations considere d, including A117V, seemed to influence the biological activities of the re spective peptides. These data identify new neurotoxic fragments of PrP in t he mutated form and elucidate their genetic influence on the pathogenesis o f TSEs.