Pathogenic Mechanisms of the Prion Protein Gene Mutations: A Review and Speculative Hypotheses for Pathogenic Potential of the Pro39Leu Mutation in the Associated FTD-Like Phenotype

Abstract

Recently, a novel, missense Pro39Leu mutation, to date unique in the N-terminal domain of the prion protein (PrP), has been reported in three patients affected by frontotemporal lobar degeneration (FTLD) syndrome, in the absence of mutations in genes known to cause dementia. Dominantly inherited mutations in the PRNP, the gene encoding PrP, have been associated with neurodegenerative disorders including Creutzfeldt-Jacob disease (CJD), Gerstmann-Sträussler-Scheinker syndrome (GSS), and Fatal Familial Insomnia (FFI), but, in some cases, PRNP mutations have been found in clinical pictures resembling other neurodegenerative diseases, such as frontotemporal dementia. The prevailing view of pathogenesis posits that these point mutations are located in the C-terminal region of the PRNP gene, and, to date, the potential importance of the N-terminal domain has largely been overlooked. The purpose of this report is to review the pathogenic mechanisms of PRNP mutations by comparing the C-and N-terminal domains. Successively, we hypothesize, based on published data and albeit speculative, that the pathogenicity of the PRNP Pro39Leu mutation in determining a particular phenotype may be due to its location in the N-terminal domain. We hope that our review may awakened a surge of interest in investigate the appearance of this particular P39L-related phenotype and possible interaction between PrP and tubulin, by future functional and neuropathological studies.

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

“…The presence of any pathogenic point mutation in residues 23–50 remained unknown until the description of the missense Pro39Leu mutation, reported in two patients affected by FTLD syndrome [13] and successively in another FTD patient [14], in which all three patients were negative for mutations in other known causative genes. Pro39Leu is the first mutation described in the N-terminal domain located in a codon (the 39 codons), before the known 102 residue (pathogenic mutation Pro102Leu causative of GSS) [15]. Nevertheless, functional studies to determine whether and how the Pro39Leu mutation may exert its pathogenic effects still remain to be implemented.…”

“…To date, most of the known PRNP pathogenic mutations have been identified in the C-terminal domain. Recently, a missense P39L mutation in N-terminal domain of the prion protein was reported by several authors, in patients affected by frontotemporal lobar degeneration (FTLD) syndrome, which were negative for mutations in genes causative of dementia [13,14,15]. Given all these data, the purpose of our report is to provide updated insights into the pathogenic mechanisms of PRNP mutations, emphasizing the differences between the C- and N-terminal domains and focusing in particular on the lesser-known flexible N-terminal, for which recent biophysical evidence has revealed a physical interaction with globular C-terminal domains of PrP C [10].…”

Characterization of mutations in <em>PRNP</em> (prion) gene and their possible roles in neurodegenerative diseases

“…It was suggested that P39L may result in less-rigid N-terminus of PrP, and it could permit abnormal cell–protein interactions. 134 – 136 …”

Changing how we think about infectious diseases

“…The prion agents have been extracted and studied. Prions can be examined in growing yeast cultures, and the propagation of prions can be observed in controlled, experimental settings [24][25][26]. In culture and in ex vivo systems, we can now study how various cellular processes may participate in the conversion of normal prion proteins into infectious prion agents [26,27].…”