Prion diseases or Transmissible Spongiform Encephalopathies (TSEs) are a group of fatal neurodegenerative illnesses affecting humans and animals. They are classified into sporadic, genetic and infectious forms. Genetic prion diseases are caused by mutations in the human prion protein gene and include Gerstmann-Sträussler-Scheinker (GSS) syndrome, Fatal Familial Insomnia and genetic Creutzfeldt–Jakob disease (CJD). Approximately 10-15% of all TSE cases in humans are associated with mutations. The development of TSEs is associated with the conversion of the cellular prion protein (PrPC) into a misfolded, pathogenic isoform (PrPSc). In our recent works, we have determined the NMR solution-state structures of the truncated recombinant human (Hu) PrPs carrying the pathological Q212P (90-231, M129) and V210I (90-231, M129) mutations. While Q212P mutation is linked to GSS the V210I mutation is linked to genetic CJD. The determined structures of both mutants consist of unstructured N-terminal part (residues 90-124) and well-defined C-terminal domain (residues 125-228). Analysis and comparison with the structure of the WT HuPrP revealed that although structures share similar global fold, mutations introduces some local structural differences. The observed variations are mostly clustered at the α2-α3 inter-helical interface and in the β2-α2 loop region. NMR structures offer new clues on the earliest events of the pathogenic conversion process and could be used for the development of antiprion drugs.
