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

Abstract

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).

Cellular Prion Protein (PrPc): Putative Interacting Partners and Consequences of the Interaction

“…In the inherited forms of prion diseases, genetic mutations in the PRNP gene may induce conformational changes, but the process of conformational alteration has not been completely understood. The mature form of PrPc is composed of flexible N-terminal domain and C-terminal globular region [ 284 ].…”

“…Most of the functional advantages of intrinsically disordered regions are due to the lack of intact tertiary and secondary structures. These advantages are described by the disorder to order change, promoting binding rate flexibility of the interaction with various partners and specific low-affinity binding [ 284 ]. Moreover, these characteristics of disordered, unstructured proteins are necessary for post-translational modifications that are involved in low affinity and high-specificity interactions between a protein and its partners.…”

“…The N-terminal domain of PrPc is highly conserved among species. The capability of PrPc to interact with different intra- and extracellular partners relies on its unstructured N-terminal domain with specific conserved and non-random amino acid sequences [ 284 ]. There are also some mutations in the N-terminal domain of PrPc.…”

Methionine oxidation within the prion protein

“…There is also increasing evidence that methionine oxidation may play a role in the pathogenesis of genetic prion diseases that are associated with specific pathogenic mutations in the human prion protein. There are more than 35 mutations in the human prion protein sequence that have been linked with genetic prion diseases [70]. A complete survey of methionine oxidation in all disease-associated mutant prion sequences is not yet available.…”

Locked in a vicious cycle: the connection between genomic instability and a loss of protein homeostasis

“…The removal or introduction of a premature stop codon (i.e. 'nonsense' mutation) can prevent a protein from ever being properly synthesized in the first place, as illustrated in the case of Apolipoprotein A-II and PrP, respectively (Benson et al 2001;Bernardi and Bruni 2019). In both examples, translation is halted at the wrong place of the transcript, leading to the production of (partially) unfolded, aggregation-prone polypeptide fragments.…”