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,Amalia C Bruni,Chiara Cupidi

doi:10.21767/2171-6625.1000208

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.

Highlights

Prion proteinsFunction: The expression of the normal prion protein (PrP) is widespread in neurons, neuroendocrine cells, and stromal cells of the lymphoreticular system, but the highest levels are found in the central nervous system, notably associated with the synaptic membrane
Similar findings have been reported for Glu200Lys, Phe198Ser, and Asp178Asn mutations. These findings indicate that the structural disorder of the β2-α2-loop together with the increased distance between the loop and α3 helix represent key pathological structural features and critical epitopes involved in the conversion to PrP Scrapie (PrPSc)
The N-terminal PRNP Pro39Leu mutation: For the first time, to our knowledge, a novel missense Pro39Leu mutation in the N-terminal domain of PrP (Figure 2) has been reported in two patients affected by frontotemporal lobar degeneration (FTLD) syndrome [74] and successively in another FTD patient [75] being all the three patients negative for mutations in known causative genes

Summary

Introduction

Function: The expression of the normal prion protein (PrP) is widespread in neurons, neuroendocrine cells, and stromal cells of the lymphoreticular system, but the highest levels are found in the central nervous system, notably associated with the synaptic membrane. The conformational conversion of normal cellular prion protein (PrPC) into a protease-resistant, amyloidogenic conformation, PrP Scrapie (PrPSc) is the defining step in prion infection [1] for which expression of PrPC is both required and rate limiting [2,3]. The prion protein is bound to the outer membrane of the cell surface, in specific cholesterol- and glycosphingolipid-rich lipid sites defined as “rafts” [4] by a glycosylphosphatidylinositol (GPI) anchor. PrPC is a copperbinding protein with superoxide dismutase activity that appears to protect against oxidative damage [7] and acts as a cell-surface

Objectives

Discussion

Conclusion