To date, the exact physiological role of PrP has not yet been definitively clarified. The expression of the wild type PrP is diffuse in neurons, neuroendocrine cells, and stromal cells of the lymphoreticular system. The highest levels have been observed in the central nervous system in the synaptic membrane. The determinant step in prion infection is the conversion of the conformation of PrP^C into a protease-resistant β-sheet, PrP^Sc [2], with concomitant expression of PrP^C, which is required and rate-limiting [16].

The PrP is bound to the outer membrane of the cell surface, in specific “rafts” (cholesterol- and glycosphingolipid-rich lipid sites) [17], by a glycosylphosphatidylinositol (GPI) anchor [18,19]. The N-terminal signal peptide (the first 22 amino acids of the precursor protein) is cleaved after translocation across the endoplasmic reticulum membrane [17]. The function of the physiological PrP seems to be to protect against programmed cell death [20]. The PrPC N-terminal domain binds both copper and zinc in vivo and participates in metal ion homeostasis [21]. Cu²⁺ and Zn²⁺ ions coordinate to the N-terminal PrP differently—Cu²⁺ interacts with the octarepeat domain, residues 60–91 with the sequence (PHGGGWGQ) [22,23], and also with residues His96 and His111 [24], whilst Zn²⁺ binds to the octarepeat domain, in which all four histidine residues coordinate a single Zn²⁺ ion [24].

PrP^C is a copper-binding protein showing superoxide dismutase activity, appearing to protect against oxidative damage [25] and acting as a cell-surface receptor for signal transduction [26]. Several studies have demonstrated that the mammalian PrP^C protein is extremely versatile, involved in proliferation, differentiation, cell adhesion, and synaptic plasticity [27]. Several functions of the PrP^C protein depend on its interaction with extra- and intra-cellular signaling partners (ligands). Among these ligands, those found to be advantageous to the cell [27] are laminin and glycosaminoglycans (GAGs), involved in neuronal differentiation and axon growth [28], and neuronal adhesion proteins, such as N-CAM12 that contribute to neurite outgrowth [28].

PRNP (NC_000020.11), located on chromosome 20 (4686151-4701588), is a 16 Kb long gene, containing two exons. Exon 1 has the role of a transcriptional initiation site, whereas the open reading frame (ORF) encoding the PrP protein, composed of 253 amino acids, is located in the exon 2 [29]. Different mutations have been reported as causative for diseases, but their effects have been associated with a variety of heterogeneous phenotypes [29]. Pathogenic mutations in the ORF of the PRNP are the only known causes of IPD [2]. These fatal neurodegenerative disorders follow a dominant mode of inheritance and are traditionally classified clinically as CJD, GSS, and FFI [30]. PRNP mutations consist of point mutations leading to an amino acid substitution or a premature stop codon, and insertions/deletions of additional (more than three additional) octapeptide repeats (OPRI/OPRD) in the region between codons 51–91 of the PrP that encodes a 5-mer repeat region consisting of a nonapeptide followed by four identical octapeptides. The frequency and distribution of these mutations differ between Europeans and East Asians [31]. Some pathogenic PRNP mutations are typically associated with particular clinical categories of prion disease [31], conferring the diagnosis of IPD and sub-classification according to a specific mutation (Table 1). Other mutations are involved in a spectrum of clinical and pathological phenotypes that vary across and within families carrying the same genetic alteration [32], often with striking phenotypic heterogeneity. In addition, different PRNP gene mutations have been suggested to play a potential role in clinical pictures mimicking other neurodegenerative diseases, such as Frontotemporal dementia (FTD) [33,34,35,36,37,38], Cerebral amyloid angiopathy (CAA) [5], familial neuropsychiatric illness [39], familial Alzheimer’s disease (AD) [40], and Huntington’s disease [41]; whereas the clinical picture may not be specific or confined to psychiatric features [32]. Of note, the most prevalent missense mutations causing IPD and a series of Single Nucleotide Polymorphisms (SNPs) are localized in the C-terminal domain. Conversely, in the N-terminal region between codons 51–91 (the region consisting of the octapeptide repeats), only OPRI/OPRD are found as polymorphisms and pathogenic mutations. 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. Recently, a PRNP mutation was described in a young GSS patient, presenting a particular clinical picture with status epilepticus at the age of 34, prefaced by night terrors at age 26, memory problems, behavioral changes and parasomnias subsided after a six-year period, emerged at this age [42]. This mutation consists of a LGGLGGYV insertion (a partial internal duplication) located at the junction between the hydrophobic region of the N-terminus and the globular domain. A subsequent study [43], involving animal modeling, defined a novel misfolded form of mutant PrP^C that prefigures the PrP mutated fragment pathognomonic for end-stage GSS with multicentric amyloid plaques [44] that might also be shared by other forms of GSS, thus providing a potential explanation for the early disease onset of the proband.

In addition to these mutations, that appear fully penetrant, many common single nucleotide polymorphisms (SNPs) have also been detected in the ORF of the PRNP gene [45]. The most important are the SNPs at codon 129, which have a critical role in susceptibility and as a modifier of prion disease, and alterations in the number of repeats, with up to three additional repeats. This specific genotype of the PRNP Met129Val SNP is responsible for the diagnosis of FFI or GSS (Table 1) when associated with the PRNP Asp178Asn mutation. Specifically, the Asp178Asn mutation accounts for FFI together with the 129Met genotype, whereas the same mutation associated with the 129Val genotype has been found in CJD (Table 1). Furthermore, the Met129Val SNP seems to be accountable for the phenotypic heterogeneity, such as variance in the age of onset (20–85 years) [32]. Other naturally occurring PRNP polymorphisms, such as the Gly127Val [46] and the Glu219Lys [47], completely prevent prion disease. In fact, it has been reported that the Gly127Val SNP in the heterozygous state was subjected to positive evolutionary selection during the epidemic of Kuru (an acquired prion disease epidemic of the Fore population in Papua, New Guinea), providing strong protection against the disease [46]. The Glu219Lys is also a PRNP SNP well-known for its protective effects against sporadic CJD [47], and the equivalent substitution in mouse PrP (Gln218Lys) is also protective against mouse-adapted scrapie [48]. It is possible that these effects depend on the inability of Glu219Lys to transform into PrP^Sc and on its dominant-negative inhibition of the coexisting wild-type PrP [49].