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).
Highlights
Prion diseases, known as transmissible spongiform encephalopathies, are progressive, fatal, neurodegenerative disorders based on the misfolding of the prion protein [1]
Human prion diseases can be divided into three groups: (1) sporadic Creutzfeldt–Jakob disease (CJD), that constitutes 85–90% of CJD cases; (2) diseases acquired by infection by external prions, such as in the case of Kuru, iatrogenic CJD, and variant CJD (2–5% of CJD cases); and (3) diseases caused by a genetic mutation in the prion (PRNP) gene, such as in the case of familial CJD, genetic CJD, Gerstmann–Sträussler–Scheinker syndrome (GSS), and fatal familial insomnia (FFI), with an autosomal dominant inheritance pattern [4]
Different studies have shown that the N-terminus of Prion protein (PrP) can interact with a broad range of ligands: (1) Metal ions, which bind to the amino acid residues 59–90, demonstrate the involvement of this region in copper endocytosis and metabolism [10]
Summary
Known as transmissible spongiform encephalopathies, are progressive, fatal, neurodegenerative disorders based on the misfolding of the prion protein [1]. Creutzfeldt–Jakob disease (CJD), fatal familial insomnia (FFI), and Gerstmann–Sträussler–Scheinker syndrome (GSS) constitute the more common and diverse human phenotypes of prion diseases [1] These phenotypes exhibit different characteristics based on the onset/duration of the disease, the clinical manifestations, neuropathological changes, transmissibility, and molecular features of scrapie-like prion protein (PrPSc) [2,3]. Little is understood about the disordered N-terminal domain, the importance of which has largely been overlooked, because known pathogenic mutations in this region have been shown to have no effect on the structure, stability, or dynamics of native mouse prion protein [12] This domain is involved in the determination of the physical properties of disease-related forms of PrP—the high degree of conservation between species of this flexible domain probably reflects a strong functional significance, and this flexibility has diverse biological endpoints [11]. 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 PrPC [10]
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