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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

Livia Bernardi, Chiara Cupidi and Amalia C Bruni

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.