Mutations in Prion Protein Gene: Pathogenic Mechanisms in C-Terminal vs. N-Terminal Domain, a Review

Int J Mol Sci. 2019 Jul 23;20(14):3606. doi: 10.3390/ijms20143606.


Inherited mutations in the Prion protein (PrP), encoded by the PRNP gene, have been associated with autosomal dominant neurodegenerative disorders, such as Creutzfeldt-Jacob disease (CJD), Gerstmann-Sträussler-Scheinker syndrome (GSS), and Fatal Familial Insomnia (FFI). Notably, PRNP mutations have also been described in clinical pictures resembling other neurodegenerative diseases, such as frontotemporal dementia. Regarding the pathogenesis, it has been observed that these point mutations are located in the C-terminal region of the PRNP gene and, currently, the potential significance of the N-terminal domain has largely been underestimated. The purpose of this report is to review and provide current insights into the pathogenic mechanisms of PRNP mutations, emphasizing the differences between the C- and N-terminal regions and focusing, in particular, on the lesser-known flexible N-terminal, for which recent biophysical evidence has revealed a physical interaction with the globular C-terminal domain of the cellular prion protein (PrPC).

Keywords: PRNP gene; PrP C-terminal domain; PrP N-terminal domain; Prion protein mutation (PrP mutation); Proline; dementia; interdomain cis interaction.

Publication types

  • Review

MeSH terms

  • Binding Sites
  • Brain / metabolism
  • Brain / pathology
  • Cations, Divalent
  • Copper / chemistry
  • Copper / metabolism
  • Creutzfeldt-Jakob Syndrome / genetics*
  • Creutzfeldt-Jakob Syndrome / metabolism
  • Creutzfeldt-Jakob Syndrome / pathology
  • Frontotemporal Dementia / genetics*
  • Frontotemporal Dementia / metabolism
  • Frontotemporal Dementia / pathology
  • Gene Expression
  • Gerstmann-Straussler-Scheinker Disease / genetics*
  • Gerstmann-Straussler-Scheinker Disease / metabolism
  • Gerstmann-Straussler-Scheinker Disease / pathology
  • Humans
  • Mutation*
  • PrPC Proteins / chemistry
  • PrPC Proteins / genetics*
  • PrPC Proteins / metabolism
  • Prion Proteins / chemistry
  • Prion Proteins / genetics*
  • Prion Proteins / metabolism
  • Protein Binding
  • Protein Interaction Domains and Motifs
  • Zinc / chemistry
  • Zinc / metabolism


  • Cations, Divalent
  • PRNP protein, human
  • PrPC Proteins
  • Prion Proteins
  • Copper
  • Zinc