Open access peer-reviewed chapter

Prion Protein Strain Diversity and Disease Pathology

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Saima Zafar, Neelam Younas, Mohsin Shafiq and Inga Zerr

Submitted: January 24th, 2018 Reviewed: August 3rd, 2018 Published: November 5th, 2018

DOI: 10.5772/intechopen.80702

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Abstract

The infectious agents, prions, are composed mainly of conformational isomers of the cellular prion protein (PrPc) in its abnormal accumulated scrapie forms (PrPSc). The distinct prion isolates or strains have been associated with different PrPSc prion protein conformations and patterns of glycosylation and are associated with disease progression and severity. In humans, sporadic Creutzfeldt-Jakob disease (sCJD) is the most common form and has been divided into six subtypes, based on PrPSc electrophoretic mobility and allelic variation at codon 129, among which sCJD MM1 and sCJD VV2 are the two most commonly occurring subtypes with known clinical manifestations. The strain-specific response of PrPSc suggests both the molecular classification and the pathogenesis of prion diseases along with posttranslational modification of PrP in humans and animals.

Keywords

  • prion strain
  • CJD
  • conformation
  • dynamics
  • aggregation

1. Introduction

For the last two decades, scientists have been working on the prion-related diseases, though major features of this transmissible neurodegenerative disease are still not clear. Among some ambiguities, the prion strain phenomenon and the zoonotic potential are the most discussed and enigmatic questions.

Prion diseases are fatal neurodegenerative disorder linked with misfolding of the host-derived protein, named prion protein. The prevalence of the disease in human population is very low (i.e., ~1–2 cases per million) and affect typically aged people. Among this 15% showed genetic concomitant, i.e., point mutation in PRNP gene.

Prion diseases are also well-known risk factor for ruminants, including sheep and goats with scrapie, cattle with bovine spongiform encephalopathy, and recently cervids with chronic wasting diseases (CWD). The prion agent was not able to cross the species barriers between humans and ruminant to a high extent, until the new application livestock carcasses recycling into the ruminant alimentary chain. This new implementation resulted in partial inactivation of the BSE prions and cemented the approach with zoonotic potential and spread in humans. This outbreak was famous as the mad cow disease in cattle and the variant CJD (vCJD) in humans. The prion strain diversity, potential to adapt from one host to another, is a mysterious character-impelled scientific community to uncover the concealed story behind.

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2. General background

2.1 The prion protein

Cellular form of prion protein PrPc (prion protein) also referred to as CD 230 (cluster of differentiation 230) is coded from PRNP gene on the short arm of chromosome 20. The PRNP gene of mammals contains three exons. The open reading frame (ORF) lies entirely within exon 3 which transcribes mRNA (2.1–2.5 kb length) with approximately 50 copies/cell in neurons [1, 2]. Physiological involvement of prion protein is diverse, but the active contribution is reflected by the high level of PRNP sequence similarity and conservation across the species in mammals. The expression of PrPc is ubiquitous in mammals’ bodies, with the highest levels in immune regulatory cells and masses, suggesting a high degree of metabolic involvement in both systems [3].

Cellular prion protein exists in multiple conformations in the cell. In humans, the newly synthesized and unprocessed PrPc is approximately 253 amino acids in length and has a molecular weight of 35–36 kDa. Mature PrPc, after posttranslational modifications, the physiological form of PrP constitutes 208 amino acid residues. PrPc is translocated to the ER lumen due to the presence of N-terminal signal peptide. Glycophosphotidyl (GPI) anchor is added after the removal of C-terminal signal peptide. After the addition of GPI anchor, PrPc is associated to the lipid rafts. Raft association of PrPc is necessary for the proper folding and glycosylation (at two asparagine residues, i.e., Asn 181 and Asn 197) taking place in ER [4] and formation of a disulfide linkage between the two cysteine residues, i.e., 179 and 214, in human PrP in the Golgi apparatus [5]. In addition, mature PrPc contains five octapeptide repeats with a sequence PHGGGWGQ near NH2-terminal that are encoded by codons 51–91 of the PRNP gene [6]. Physiological form of prion protein, PrPc, occurs predominantly along with the truncated, transmembrane COOH–terminal and transmembrane NH2-terminal forms, namely, PrPCtm and PrPNtm, respectively, due to transmembrane insertion of the hydrophobic pocket between aa 110 and 134 [7, 8]. A GPI anchor is attached to PrPc during its life cycle in the cell [9].

In neurons, the cell surface retentivity is very short-lived, like other classical membrane receptors, i.e., a t 1/2 of 3–5 min. The endocytosis is rather enigmatic. In different cells and different physiological conditions, internalization via both clathrin- and non-clathrin-coated vesicles is reported [10].

Structural studies of recombinant human PrPc reveal that the protein consists of three α-helices at aa residues 144–154, 175–193, and 200–219 and two small antiparallel β-sheets between aa residues 128–131 and 161–164 [11]. PrPc contains a flexible domain at N-terminal between amino acid positions 23–120, whereas a folded domain at C-terminal between amino acids 121–231.

The presence of the PrPc on cell surface suggests its role as a cell receptor. Many studies relate PrPc to diverse signaling pathways. The N-terminal domain containing the octapeptide repetitive motif is reported to exhibit a high affinity for copper ions (Cu2+), suggesting the involvement of PrPc in copper metabolism [12, 13]. PrP is also reported to regulate the influx of Zn2+ into the neuronal cells via α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors, by acting as a zinc sensor to the AMPA receptor acting as transporter for Zn2+. These results also suggest that PrP-mediated zinc uptake may contribute to neurodegeneration in prion and other neurodegenerative diseases [14, 15]. PrPc also promotes cellular Ca2+ influx via VGCC [16, 17]. Likewise, the activation of Ras GTPases after interaction of PrPc leading to Erk activation is also reported [18]. Activation of protein kinase C and PI3 kinase/Akt signaling is also reported to be associated to PrP, but the mechanism of activation is poorly understood [19, 20].

Derivatives resulting from the various PrPc-proteolytic cleavages are associated to the alteration of PrPc physiology. An α-cleavage at aa residues 110/111 results in N1 and C1 fragments, whereas a β-cleavage event at aa residue 90 results in N2 and C2 fragments. On the cell surface, some proportion of PrPc also undergoes an ADAM10-driven cleavage at GPI anchor called as shedding, resulting in the release of full-length PrPc molecule in extracellular milieu [21].

2.2 Prion diseases

Prion diseases, also known as transmissible spongiform encephalopathies (TSEs), are rare progressive, incurable fatal neurodegenerative diseases that have the property of transmissibility [2, 22, 23]. Prion diseases affect humans and animals. Human prion diseases include Creutzfeldt-Jakob disease (CJD), fatal familial insomnia (FFI), Gerstmann-Sträussler-Scheinker syndrome, variably protease-sensitive prionopathy (VPSPr), vCJD, and Iatrogenic CJD (iCJD) [24]. Animal prion diseases include bovine spongiform encephalopathy (BSE) in cattle [25], chronic wasting disease (CWD) in deer and elk [26], and scrapie in sheep, goats and experimentally infected rodents [12].

Human prion diseases occur at a rate of one to two cases per million per year. Among human prion diseases, 80–95% are sporadic Creutzfeldt-Jakob disease (sCJD), 10–15% are genetic (often familial), and less than 1% are acquired. In sCJD, the conversion of PrPc to PrPSc is thought to occur spontaneously (or possibly through a somatic mutation of PRNP). In genetic prion diseases, it is thought that mutations in the prion protein gene, PRNP, make the PrPc more susceptible to changing conformation (misfolding) into PrPSc. In acquired forms, PrPSc is accidentally transmitted to a person, causing their endogenous PrPc to misfold [27].

Prion diseases belong to a growing family of protein misfolding diseases that are attributed to misfolding (conformational alterations) and aggregation of proteins in specific brain regions, including Alzheimer’s disease, Parkinson’s disease, and systemic amyloidosis [28, 29]. Some characteristic features of prion diseases are their wide phenotypic heterogeneity and their multiple modes of occurrence (sporadic, genetic, or acquired) [30, 31]. Central hypothesis in prion diseases is the conversion of an endogenous protease-sensitive cellular prion protein, PrPc, into a conformationally altered self-replicating protease-resistant pathological isoform, PrPSc [32], in the central and lymphoreticular systems. PrPSc binds to cellular PrPc and catalyzes its conversion to an infectious form by nucleation and fragmentation cycle [33]. Prions are resistant to proteases, heat, and decontamination treatments, which is a major challenge for the prevention of prion diseases. Although protease-resistant prions correlate only slightly with infectivity, infectivity is linked to protease-sensitive oligomers [34]. PrPc-to-PrPSc conversion brings in neurotoxicity to the attributes of PrPSc [35]. Diseases arising due to prion misfolding are enlisted in Table 1 .

Phenotypes
Familial (inherited) Familial Creutzfeldt-Jakob-disease (fCJD)
Fatal familial insomnia (FFI)
Gerstmann-Sträussler-Scheinker disease (GSS)
Mixed or undefined forms
Sporadic CJD (sporadic)
Typical (MM1 and MV1)
Early onset (VV1)
Long duration (MM2)
Kuru plaques (MV2)
Ataxic (VV2)
Sporadic familial insomnia (sFI)
Acquired Kuru
Iatrogenic CJD (iCJD)
variant CJD (vCJD)

Table 1.

Classification of human prion disease.

Modified [93].

Human prion diseases are characterized by a range of clinical symptoms and are classified by both clinico-pathological symptoms and etiology, with subclassifications according to the molecular features. Clinical manifestations include spongiform degeneration, motor and cognitive impairments, neuronal loss, gliosis, astrocytosis, and neuronal dysfunction [23]. Prion diseases have long incubation periods; once clinical symptoms appear, disease progresses very rapidly with lethality in all cases.

Sporadic Creutzfeldt-Jakob disease (sCJD) has average survival of about 6 months, with 85–90% of patients dying within 1 year. The peak age of onset is 55–75 years of age, with median age of onset of about 67 years and mean of 64 years [36]. Sporadic Creutzfeldt-Jakob disease has been classified based on combination of two features: a PRNP polymorphism at codon M129V [37] and the size of PK-digested PrPSc on Western blot giving two main types: type 1, with a more distal cleavage site, are 21 kDa and type 2, with a more proximal cleavage site, are 19 kDa. These factors result in six possible combinations (MM1, MV1, VV1, MM2, MV2, and VV2) [36]. Codon 129 M/M homozygosity is reported to be associated with an early-onset and aggressive dementia in the CJD patients, whereas V/V homozygosity correlates to a more prolonged pathology with ataxic onset [38]. Apart from codon 129, two other polymorphisms have been reported, i.e., N171S and E219K [39, 40]. Disease-specific PrP mutations have been reviewed in detail by [41]. GSS associated PRNP mutations include P102L, P105L, A117V, F198S, D202N, Q212P, and Q217R. PRNP mutations associated to fCJD include P102L, P105L, A117V, F198S, D202N, Q212P, and Q217R, whereas a single missense mutation (D178N) has been reported for FFI. This vast structural diversity and switching to disease causing PrPSc make prion protein and its derivatives interesting subject of study.

Although many laboratories are working on therapeutic strategies for prion disease, still they are incurable although some of the symptoms can be temporarily treated [27]. Three randomized double-blinded placebo-controlled trials have failed to alter disease outcome [27, 42].

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3. Prion strains and impact on biological parameters

3.1 Prion strain diversity

Prion diseases affect a range of mammalian species and are caused by misfolding of normal cellular PrPc to self-propagating pathological isoform (PrPSc) [43]. Prions can form several distinct self-templating conformers, called prion strains (or variants), which confer dramatic variation in disease pathology and transmission [44]. Diverse strains of prions [45] exist and are operationally defined by differences in a heritable phenotype under controlled experimental transmission setups. Prion strains can differ in tissue tropism, incubation period, clinical signs of disease, and host range.

Prion disorders remain a challenge to modern science in the twenty-first century because of their strain diversity and interspecies transmission properties. Different clinicopathological properties of prion ailments are associated to biochemical heterogeneity in pathogenic protein. Unfortunately, little is known about the mechanisms that drive these differences in biochemical properties.

The mechanism by which a protein pathogen can encode strain diversity is only beginning to be understood. The identification of strain-specific cellular cofactors persuading the generation of new prion strains or the selection, from a conformationally heterogeneous population of PrPSc, of the most suitable prion conformation in a specific environment, denotes an important milestone toward the understanding of the mechanisms of prion strain diversity, which can have vital clinical and therapeutic implications. Adaptation to a new host is the basis of interspecies transmission of prion infections. In some cases, no abnormally folded PrP is found, reflecting a molecular species barrier to disease transmission [46, 47].

Although significant advancements have been made in comprehending the phenomenon of prion strains, many pieces of information are still missing, most important among them is the definitive evidence for the structural differences between prion strains and the relationship between the strain-specific properties of PrPSc and the resulting phenotype of disease [48, 49].

There are two main theories about possible interspecies transmission and adaptive properties of prion infections: the first one considers that strains are present as a single clone in inoculum, and if a new strain arises, it can be assumed that a stain shift has occurred. The second one considers that strains exist as a pool of different molecular species with a dominant type of PrPSc that is preferentially propagated in a given host, but in a different host, a minor PrPSc type can be favored, causing a shift in the strain. The second theory seems to better explain the high level of strain diversity that is reported from experimental data, although the likelihood that prion strains can infect the host as a single clone cannot be excluded. Plausible explanation for the second theory can be that from a pool of different conformations of PrPSc, only a specific fraction is able to replicate in a certain host species, in a manner that is dependent on the sequence and conformation of the PrPc, on the natural clearance capacity of the infected cells [50, 51, 52, 53] and on the presence of cofactors [54, 55, 56]. In such a model, a prion strain behaves as a quasi-species and represents a pool of molecules that are kept under control by the host [57]. Hence, in a given host, a strain will be constituted of a principal molecular component and a minor one.

Accordingly, interspecies transmission depends on compatibility between the conformation of pathological PrPSc and of the PrPc of the new host, on cell and tissue environment and cofactors [58, 59]. When a prion strain of one species infects an animal of a different species, there are two possible outcomes. The first is that the pathological PrPSc has no conformation compatibility with the host PrPc, resulting in non-conversion; in this case, the species barrier is defined as absolute. The second possibility is that the PrPSc conformation is compatible with the PrPc host conformation, allowing conversion and, ultimately, infection. In this case the proliferated strain can be identical to the infecting unit [60] or can change into a conformationally different strain due to cellular environment, polymorphisms, and cofactors [58, 59]. So, this type of transmission can facilitate the replication of the minor molecular component, if it is favored in the new host, or the generation of a new PrPSc different from the one of the inoculum [61, 62].

Many studies have been performed to reveal the nature of the cofactors that may be involved. It has been demonstrated that RNA molecules; protein chaperones, such as Hsp104 and GroEL; and others have been shown to change strain properties of prions highlighting the role of different cofactors in determining prion strain’ propagation properties.

3.2 Transmissibility, heritable phenotype, and species barrier

In the early 1900s, the intraspecies transmission of the TSE agent was first documented with sheep scrapie [63]. The intraspecies transmission (i.e., sheep-sheep) showed marked attack rate as compared to the cross species transmission (i.e., sheep-mice) which showed incomplete attack rate and longer incubation periods. In cross species transmissions, the main hindrance was the adaptation of prion to its new host that leads to the vitiated prions after few subpassages, i.e., 2–3 passages. Previously, this phenomenon hindered the development of rodent models. Later, it has been reported that distinct prion strains, upon serial adaptation of sheep or goat scrapie isolates, could be raised and propagate in different lines of mice. The incubation time, disease severity, and vacuolation distribution in the brain of the mice-adapted strains showed marked signature of the specific disease [64]. However, the major goal at that time was to establish disease-specific end-stage response with clinical symptomatic phase leading to the anatomic distribution with significant lesion score profile. The first experiments reported inoculation of sheep scrapie to goats [65, 66, 67]. By that time, prion transmission from one species to the other, i.e., mink to small ruminants, was reported [68], and the bank vole showed maximum transmission capability and turned out as the universal prion strain acceptor [69, 70, 71]. In contrast, few studies also reported partial species barriers to pass prions from one species to another, i.e., scrapie isolates to cattle [72].

The emerging field of engineered transgenic mouse models, in combination with endogenous mouse PrP expression (presence or absence), significantly enhanced the possibilities for studying the zoonotic potential of prions [73, 74, 75, 76]. In many cases, these experimental setups made emerged the idea that almost every prion could adapt to almost every PrP substrate, provided that some critical parameters have been set up in order to adapt the strain to its new host PrP [77, 78, 79]. The transmission efficacy of vCJD strain to wild-type mice also showed conserved and uniform characteristic BSE strain phenotype. The incubation period, glycoform analysis, and lesion profile did not show differential alterations in brain regions and in lymphoreticular tissue [80].

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4. Prion strains and disease response

4.1 Phenotypic variants of PrP and human prion strains

The cellular prion protein is a product of PRNP gene-residing the chromosome 20 in human. The conformational variations of PrPc in transmissible spongiform encephalopathies (TSEs) give rise to multiple phenotypic variants of PrP-scrapie form (PrPSc), referred to as prion strains. A pure strain refers to a molecular population of PrPSc with characteristic features such as incubation time, PrPSc distribution patterns, resultant spongiosis, and relative severity of the spongiform changes in the brain, when inoculated into distinct host species. In a given prion pathology, a strain species predominantly exists along with minimal concentrations of strains. Classically prion strains are classified based on abovementioned features. Characteristic pattern of prion strains on the western blotting has also been used for the strain classification. The differences of western blotting patterns occur due to the variability of proteinase k cleavage sites in prion protein and abundance of differential PrP glycoforms (i.e., di-glycosylated, mono-glycosylated, and un-glycosylated isoforms). Rather recently, nontrivial approaches such as seeding potential of prion variants and differential strain-specific oligomeric populations have expanded the spectrum of strain classification [81].

In human prion strains, variation is determined by proteinase K (PK) resistance. PK-resistant PrP occurs in two forms based on the migration on western blots, i.e., PrPSc type 1 migrates at 21 kDa, whereas type 2 PrPSc migrates at 19 kDa (resultant of two distinct PK digestion at amino acids 96 and 85, respectively) [82]. Atypical cases of variably protease-sensitive prionopathy (VPSPr) exhibit a different sensitivity profile to the Proteinase K. Some cases have been reported to exhibit no PK resistance (viz., protease-sensitive prionopathy, PSPr), whereas some other VPSPr cases present less PK resistance resulting in a ladder-like pattern on western blot ranging from 27 to 7 kDa. Details of human prion strains in combination with codon 129 M/V polymorphism are listed in Table 2 [83].

Strain type Histological characteristics Disease subtype, % age occurrence of all prion pathologies
MM/MV 1 Diffuse synaptic deposits sCJD, 40%
VV 2 Perineuronal and cerebellar plaque-like deposits sCJD, 15%
MV 2K Kuru plaques sCJD, 8%
MM 2C Cortical confluent vacuoles sCJD, 1%
MM 2T (sFI) Thalamo-olivary atrophy sCJD
VV 1 Corticostriatal synaptic deposits sCJD
MM 2V (vCJD) Florid plaques sCJD
MM/MV1+2C Mixed diffuse synaptic deposits and cortical confluent vacuoles sCJD, 30%
MV 2K+C Mixed Kuru plaques and cortical confluent vacuoles sCJD
MM-VPSPr Large vacuoles, PrPSc microplaques in the molecular layer of the cerebellum, as well as target-like rounded formations of clusters of granules that increase in size toward the center VPSPr
MV-VPSPr
VV-VPSPr

Table 2.

Human prion strain histopathological profiles, influenced by codon 129 polymorphism determined in different backgrounds of human transmissible spongiform encephalopathies (TSEs).

Modified from [83].

Abbreviations: BSE, bovine spongiform encephalopathy; sCJD, sporadic Creutzfeldt-Jakob disease; sFI, sporadic fatal insomnia; VPSPr, variably protease-sensitive prionopathy; gCJD, genetic CJD; GSS, Gerstmann-Sträussler-Scheinker disease; FFI, fatal familial insomnia; vCJD, variant CJD.

4.2 Templating activity

Prion templating activity coupled with the structure studies is also used as an index for strain classification. Baskakov and colleagues have been able to differentiate the hamster recombinant PrP strains based on the structure profiles formed under different conditions, i.e., R and S fibrils, result of polymerization while rotating and shaking the monomers, respectively [84]. Structural validations of the prion protein polymers are challenging due to overly high hydrophobic nature of the polymers. For robust templating activity-based classification of prion strains, two methods have been established, namely, protein misfolding cyclic amplification (PMCA) and real-time quacking-induced cyclic amplification (RT-QuIC), where prion strains are utilized as templates for the recombinant prion protein. Templating in PMCA is usually validated with downstream Western blotting, where RT-QuIC is a fluorometry-based method and provides the real-time information, utilizing thioflavin-T binding to polymers. Lag phase and final fluorescence signals could be used for discrimination between different prion strains [71]. RT-QuIC proves to be a highly specific and sensitive method and has been utilized to establish strain differences of typical and atypical prionopathies, e.g., the L-type BSE and classical BSEs [85].

A recent report showed oligo-/poly-thiophene derivate as a potent fluorescent approach to discriminate between prion strains [86]. The excitation/emission spectra were obtained from the CWD and scrapie strains, and the interactive association between thiophene and different aggregates were used in combination with conformational restriction to characterize different strains.

4.3 Distribution of density variants

Prion strain polymerization is a sequential process where single molecules are converted to polymers via a multitude of conformational variants. Different prion strains have been identified in animal and human cases based upon differential population densities of these quaternary structures [87]. Quaternary structure conformers of PrP have been isolated and studied using sucrose density gradient by many groups [88, 89, 90, 91]. Differential prion strains have been also identified for the rapidly progressive forms of Alzheimer’s disease with distinct population of high-density PrP oligomeric species [92].

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5. Conclusions and future outlook

Prion strains and the interspecies barriers are still enigmatic phenomena. One of the surprising things about prion protein is that this single protein can fold up in so many different ways that are toxic and cause disease. Recent advances in PrPSc amplification methods, i.e., PMCA and RT-QuIC, might lead to clear improvements in the characterization of the prion strain.

From last many years, prion protein strain characterization and impact on disease are under debate. The use of prion transgenic models has been influential for studying and clarifying the molecular mechanisms in which the protein is involved. The ability to cross species barrier may be a result of either quasispecies theory or host PrP impact on progressive templating deformation upon oligomerization theory ( Figure 1 ). These phenomena are mostly time dependent. By learning the structural variation and potential interspecies transmissions, we may progress toward the understanding of disease pathology and subsequently development of novel therapeutic approaches to such devastating disorders.

Figure 1.

Prion strain emergence and interspecies transmission. The original prion strains were named as Kuru in human, BSE in cows, TSE in goat and sheep, and TME in minks. PMCA and RT-QuiC mobilized the prion strain characterization. The interspecies transmission of prions linked with host PrP oligomerization role, appearance of subassemblies named as quasispecies, tissue tropism, incubation period of prions, symptomatic stages of the diseases, and host range.

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Acknowledgments

The study was performed within the recently established Clinical Dementia Center at the University Medical Hospital Goettingen and was partly supported by grants from the EU Joint Program Neurodegenerative Disease Research (JPND ± DEMTEST) (Biomarker-based diagnosis of rapid progressive dementias-optimization of diagnostic protocols, 01ED1201A). This work was supported by a grant from Helmholtz-Alberta Initiative-Infectious Diseases Research (HAI-IDR) and APRI-Human prions distinguishing sporadic from familial forms via structure and function as well as from the DZNE clinical project (Helmholtz).

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Conflict of interest

We have no conflict of interest to declare.

References

  1. 1. Liao YC, Lebo RV, Clawson GA, Smuckler EA. Human prion protein cDNA: Molecular cloning, chromosomal mapping, and biological implications. Science (80-). 1986;233:364-367
  2. 2. Prusiner SB. Molecular biology of prion diseases. Science (80). 1991;252:1515-1522. DOI: 10.1126/science.1675487
  3. 3. Linden R, Martins VR, Prado MAM, Cammarota M, Izquierdo I, Brentani RR. Physiology of the prion protein. Physiological Reviews. 2008;88:673-728. DOI: 10.1152/physrev.00007.2007
  4. 4. Haraguchi T, Fisher S, Olofsson S, Endo T, Groth D, Tarentino A, et al. Asparagine-linked glycosylation of the scrapie and cellular prion proteins. Archives of Biochemistry and Biophysics. 1989;274:1-13. DOI: 10.1016/0003-9861(89)90409-8
  5. 5. Turk E, Teplow DB, Hood LE, Prusiner SB. Purification and properties of the cellular and scrapie hamster prion proteins. European Journal of Biochemistry. 1988;176:21-30. DOI: 10.1111/j.1432-1033.1988.tb14246.x
  6. 6. Owen F, Poulter M, Shah T, Collinge J, Lofthouse R, Baker H, et al. An in-frame insertion in the prion protein gene in familial Creutzfeldt-Jakob disease. Brain Research. Molecular Brain Research. 1990;7:273-276
  7. 7. Hegde RS. A transmembrane form of the prion protein in neurodegenerative disease. Science (80-). 1998;279:827-834. DOI: 10.1126/science.279.5352.827
  8. 8. Hegde RS, Voigt S, Lingappa VR. Regulation of protein topology by trans-acting factors at the endoplasmic reticulum. Molecular Cell. 1998;2:85-91. DOI: 10.1016/S1097-2765(00)80116-1
  9. 9. Taylor DR, Hooper NM. The prion protein and lipid rafts. Molecular Membrane Biology. 2006;23:89-99. DOI: 10.1080/09687860500449994
  10. 10. Sunyach C. The mechanism of internalization of glycosylphosphatidylinositol-anchored prion protein. The EMBO Journal. 2003;22:3591-3601. DOI: 10.1093/emboj/cdg344
  11. 11. Surewicz WK, Apostol MI. Prion protein and its conformational conversion: A structural perspective. Topics in Current Chemistry. 2011;305:135-168. DOI: 10.1007/128_2011_165
  12. 12. Stockel J, Safar J, Wallace AC, Cohen FE, Prusiner SB. Prion protein selectively binds copper (II) ions. Biochemistry. 1998;37:7185-7193. DOI: 10.1021/bi972827k
  13. 13. Dobson CM. Structural biology: Prying into prions. Nature. 2005;345:747-749. DOI: 10.1038/435747a
  14. 14. He Q, Meiri KF. Isolation and characterization of detergent-resistant microdomains responsive to NCAM-mediated signaling from growth cones. Molecular and Cellular Neurosciences. 2002;19:18-31. DOI: 10.1006/mcne.2001.1060
  15. 15. Cooper DMF, Crossthwaite AJ. Higher-order organization and regulation of adenylyl cyclases. Trends in Pharmacological Sciences. 2006;27:426-431. DOI: 10.1016/j.tips.2006.06.002
  16. 16. Herms JW, Korte S, Gall S, Schneider I, Dunker S, Kretzschmar HA. Altered intracellular calcium homeostasis in cerebellar granule cells of prion protein-deficient mice. Journal of Neurochemistry. 2000;75:1487-1492. DOI: 10.1046/j.1471-4159.2000.0751487
  17. 17. Fuhrmann M, Bittner T, Mitteregger G, Haider N, Moosmang S, Kretzschmar H, et al. Loss of the cellular prion protein affects the Ca2+ homeostasis in hippocampal CA1 neurons. Journal of Neurochemistry. 2006;98:1876-1885
  18. 18. Stork PJS, Schmitt JM. Crosstalk between cAMP and MAP kinase signaling in the regulation of cell proliferation. Trends in Cell Biology. 2002;12:258-266. DOI: 10.1016/S0962-8924(02)02294-8
  19. 19. Dekker LV, Palmer RH, Parker PJ. The protein kinase C and protein kinase C related gene families. Current Opinion in Structural Biology. 1995;5:396-402. Available from: http://www.ncbi.nlm.nih.gov/pubmed/7583639
  20. 20. Vassallo N, Herms J, Behrens C, Krebs B, Saeki K, Onodera T, et al. Activation of phosphatidylinositol 3-kinase by cellular prion protein and its role in cell survival. Biochemical and Biophysical Research Communications. 2005;332:75-82. DOI: 10.1016/j.bbrc.2005.04.099
  21. 21. Altmeppen HC, Puig B, Dohler F, Thurm DK, Falker C, Krasemann S. Proteolytic processing of the prion protein in health and disease. American Journal of Neurodegenerative Disease. 2012;1:15-31
  22. 22. Caughey B, Chesebro B. Transmissible spongiform encephalopathies and prion protein interconversions. Advances in Virus Research. 2001;56:277-311
  23. 23. Collinge J. Prion diseases of humans and animals: Their causes and molecular basis. Annual Review of Neuroscience. 2001;24:519-550
  24. 24. Aguzzi A, Calella AM. Prions: Protein aggregation and infectious diseases. Physiological Reviews. 2009;89:1105-1152. DOI: 10.1152/physrev.00006.2009
  25. 25. Hope J, Reekie LJ, Hunter N, Multhaup G, Beyreuther K, White H, et al. Fibrils from brains of cows with new cattle disease contain scrapie-associated protein. Nature. 1988;336:390-392. DOI: 10.1038/336390a0
  26. 26. Williams ES, Young S. Chronic wasting disease of captive mule deer: A spongiform encephalopathy. Journal of Wildlife Diseases. 1980;16:89-98
  27. 27. Brown K, Mastrianni JA. The prion diseases. Journal of Geriatric Psychiatry and Neurology. 2010;23(4):277-298. DOI: 10.1177/0891988710383576
  28. 28. Soto C. Unfolding the role of protein misfolding in neurodegenerative diseases. Nature Reviews. Neuroscience. 2003;4:49-60. DOI: 10.1038/nrn1007
  29. 29. Aguzzi A, Rajendran L. The transcellular spread of cytosolic amyloids, prions, and prionoids. Neuron. 2009;64:783-790. DOI: 10.1016/j.neuron.2009.12.016
  30. 30. McKintosh E, Tabrizi SJ, Collinge J. Prion diseases. Journal of Neurovirology. 2003;9:183-193
  31. 31. Prusiner SB. Novel proteinaceous infectious particles cause scrapie. Science. 1982;216:136-144
  32. 32. Caughey B. Prion protein conversions: Insight into mechanisms, TSE transmission barriers and strains. British Medical Bulletin. 2003;66:109-120
  33. 33. Knowles TPJ et al. An analytical solution to the kinetics of breakable filament assembly. Science. 2009;326:1533-1537. DOI: 10.1126/science.1178250
  34. 34. Aguzzi A, Lakkaraju AKK. Cell biology of prions and prionoids: A status report. Trends in Cell Biology. 2016;26:40-51. DOI: 10.1016/j.tcb.2015.08.007
  35. 35. Norrby E. Prions and protein-folding diseases. Journal of Internal Medicine. 2011;270:1-14. DOI: 10.1111/j.1365-2796.2011.02387
  36. 36. Puoti G, Bizzi A, Forloni G, et al. Sporadic human prion diseases: Molecular insights and diagnosis. Lancet Neurology. 2012;11(7):618-628. DOI: 10.1016/S1474-4422(12)70063-7
  37. 37. Lloyd SE, Mead S, Collinge J. Genetics of prion diseases. Current Opinion in Genetics and Development. 2013;23:345-351. DOI: 10.1016/j.gde.2013.02.012
  38. 38. Palmer MS, Dryden AJ, Hughes JT, Collinge J. Homozygous prion protein genotype predisposes to sporadic Creutzfeldt-Jakob disease. Nature. 1991;352:340-342. DOI: 10.1038/352340a0
  39. 39. Kitamoto T, Tateishi J. Human prion diseases with variant prion protein. Philosophical Transactions of the Royal Society B: Biological Sciences. 1994;343:391-398. DOI: 10.1098/rstb.1994.003431
  40. 40. Hizume M, Kobayashi A, Teruya K, Ohashi H, Ironside JW, Mohri S, et al. Human prion protein (PrP) 219K is converted to PrPSc but shows heterozygous inhibition in variant Creutzfeldt-Jakob disease infection. The Journal of Biological Chemistry. 2009;284:3603-3609. DOI: 10.1074/jbc.M809254200
  41. 41. Acevedo-Morantes CY, Wille H. The structure of human prions: From biology to structural models—Considerations and pitfalls. Viruses. 2014;6:3875-3892. DOI: 10.3390/v6103875
  42. 42. Kim MO, Geschwind MD. Clinical update of Jakob-Creutzfeldt disease. Current Opinion in Neurology. 2015;28(3):302-310. DOI: 10.1097/WCO.0000000000000197
  43. 43. Colby DW, Prusiner SB. Prions. Cold Spring Harbor Perspectives in Biology. 2011;3(1):a006833. DOI: 10.1101/cshperspect.a006833
  44. 44. Stein KC, True HL. Extensive diversity of prion strains is defined by differential chaperone interactions and distinct amyloidogenic regions. PLoS Genetics. 2014;10(5):e1004337. DOI: 10.1371/journal.pgen.1004337
  45. 45. Safar JG. Molecular pathogenesis of sporadic prion diseases in man. Prion. 2012;6:108-115. DOI: 10.4161/pri.18666
  46. 46. Katorcha E, Gonzalez-Montalban N, Makarava N, Kovacs GG, Baskakov IV. Prion replication environment defines the fate of prion strain adaptation. PLoS Pathogens. 2018;14:e1007093. DOI: 10.1371/journal.ppat.1007093
  47. 47. Igel-Egalon A, Beringue V, Rezaei H, Sibille P. Prion strains and transmission barrier phenomena. Pathogens. 2018;7:5. DOI: 10.3390/pathogens7010005
  48. 48. Crowell J, Hughson A, Caughey B, Bessen RA. Host determinants of prion strain diversity independent of prion protein genotype. Journal of Virology. 2015;89:10427-10441. DOI: 10.1128/JVI.01586-15
  49. 49. Taguchi Y, Lu L, Marrero-Winkens C, Otaki H, Nishida N, Schatzl HM. Disulfide-crosslink scanning reveals prion-induced conformational changes and prion strain-specific structures of the pathological prion protein PrP(Sc). Journal of Biological Chemistry. 2018;293:12730-12740. DOI: 10.1074/jbc.RA117.001633
  50. 50. Safar JG, DeArmond SJ, Kociuba K, Deering C, Didorenko S, Bouzamondo-Bernstein E, et al. Prion clearance in bigenic mice. The Journal of General Virology. 2005;86:2913-2923. DOI: 10.1099/vir.0.80947-0
  51. 51. Paar C, Wurm S, Pfarr W, Sonnleitner A, Wechselberger C. Prion protein resides in membrane microclusters of the immunological synapse during lymphocyte activation. European Journal of Cell Biology. 2007;86:253-264. DOI:  10.1016/j.ejcb.2007.03.001
  52. 52. Wong E, Cuervo AM. Integration of clearance mechanisms: The proteasome and autophagy. Cold Spring Harbor Perspectives in Biology. 2010;2:a006734. DOI: 10.1101/cshperspect.a006734
  53. 53. Mannini B, Cascella R, Zampagni M, van WaardeVerhagen M, Meehan S, Roodveldt C, et al. Molecular mechanisms used by chaperones to reduce the toxicity of aberrant protein oligomers. Proceedings of the National Academy of Sciences of the United States of America. 2012;109:12479-12484. DOI:  10.1073/pnas.1117799109
  54. 54. Cohen FE, Pan KM, Huang Z, Baldwin M, Fletterick RJ, Prusiner SB. Structural clues to prion replication. Science. 1994;264:530-531. DOI: 10.1126/science.7909169
  55. 55. Deleault NR, Lucassen RW, Supattapone S. RNA molecules stimulate prion protein conversion. Nature. 2003;425:717-720. DOI: 10.1038/nature01979
  56. 56. Deleault NR, Walsh DJ, Piro JR, Wang F, Wang X, Ma J, et al. Cofactor molecules maintain infectious conformation and restrict strain properties in purified prions. Proceedings of the National Academy of Sciences of the United States of America. 2012;109:E1938-E1946. DOI:  10.1073/ pnas.1206999109
  57. 57. Weissmann C, Li J, Mahal SP, Browning S. Prions on the move. EMBO Reports. 2011;12:1109-1117. DOI: 10.1038/embor.2011.192
  58. 58. Hill AF, Collinge J. Prion strains and species barriers. Contributions to Microbiology. 2004;11:33-49. DOI: 10.1159/000077061
  59. 59. Hamir AN, Kehrli ME Jr, Kunkle RA, Greenlee JJ, Nicholson EM, Richt JA, et al. Experimental interspecies transmission studies of the transmissible spongiform encephalopathies to cattle: Comparison to bovine spongiform encephalopathy in cattle. Journal of Veterinary Diagnostic Investigation. 2011;23:407-420. DOI: 10.1177/1040638711403404
  60. 60. Collinge J, Clarke AR. A general model of prion strains and their pathogenicity. Science. 2007;318:930-936. DOI: 10.1126/science.1138718
  61. 61. Bessen RA, Marsh RF. Identification of two biologically distinct strains of transmissible mink encephalopathy in hamsters. The Journal of General Virology. 1992;73:329-334. DOI: 10.1099/0022-1317-73-2-329
  62. 62. Bartz JC, Bessen RA, McKenzie D, Marsh RF, Aiken JM. Adaptation and selection of prion protein strain conformations following interspecies transmission of transmissible mink encephalopathy. Journal of Virology. 2000;74:5542-5547. DOI: 10.1128/JVI.74.12.5542-5547.2000
  63. 63. Cuillé J, Chelle PL. La tremblante dumouton est bien inoculable. Comptes Rendus de l'Académie des Sciences. 1938;206:78-79
  64. 64. Houston F, Andreoletti O. The zoonotic potential of animal prion diseases. Handbook of Clinical Neurology. 2018;153:447-462. DOI: 10.1016/B978-0-444-63945-5.00025-8
  65. 65. Plummer PJ. Scrapie—A disease of sheep: A review of the literature. Canadian Journal of Comparative Medicine and Veterinary Science. 1946;10:49-54
  66. 66. Pattison IH, Gordon WS, Millson GC. Experimental production of scrapie in goats. Journal of Comparative Pathology and Therapeutics. 1959;69:300IN19-312IN20
  67. 67. Pattison IH, Millson GC. Scrapie produced experimentally in goats with special reference to the clinical syndrome. Journal of Comparative Pathology. 1961;71:101-109
  68. 68. Hadlow WJ, Race RE, Kennedy RC. Experimental infection of sheep and goats with transmissible mink encephalopathy virus. Canadian Journal of Veterinary Research. 1987;51:135-144
  69. 69. Nonno R, Bari MAD, Cardone F, Vaccari G, Fazzi P, Dell’Omo G, et al. Efficient transmission and characterization of Creutzfeldt-Jakob disease strains in Bank voles. PLoS Pathogens. 2006;2:e12. DOI: 10.1371/journal.ppat.0020012
  70. 70. Watts JC, Giles K, Patel S, Oehler A, DeArmond SJ, Prusiner SB. Evidence that bank vole PrP is a universal acceptor for prions. PLoS Pathogens. 2014;10:e1003990
  71. 71. Orrú CD, Groveman BR, Raymond LD, Hughson AG, Nonno R, Zou W, et al. Bank vole prion protein as an apparently universal substrate for RT-QuIC-based detection and discrimination of prion strains. PLOS Pathogens. 2015;11:e1004983. DOI: 10.1371/journal.ppat.1004983
  72. 72. Robinson MM, Hadlow WJ, Knowles DP, Huff TP, Lacy PA, Marsh RF, et al. Experimental infection of cattle with the agents of transmissible mink encephalopathy and scrapie. Journal of Comparative Pathology. 1995;113:241-251
  73. 73. Collinge J, Palmer MS, Sidle KC, Hill AF, Gowland I, Meads J, et al. Unaltered susceptibility to BSE in transgenic mice expressing human prion protein. Nature. 1995;378:779-783
  74. 74. Büeler H, Aguzzi A, Sailer A, Greiner R-A, Autenried P, Aguet M, et al. Mice devoid of PrP are resistant to scrapie. Cell. 1993;73:1339-1347
  75. 75. Telling GC, Scott M, Hsiao KK, Foster D, Yang SL, Torchia M, et al. Transmission of Creutzfeldt-Jakob disease from humans to transgenic mice expressing chimeric human-mouse prion protein. Proceedings of the National Academy of Sciences of the United States of America. 1994;91:9936-9940
  76. 76. Brandner S, Isenmann S, Raeber A, Fischer M, Sailer A, Kobayashi Y, et al. Normal host prion protein necessary for scrapie-induced neurotoxicity. Nature. 1996;379:339-343
  77. 77. Ghaemmaghami S, Watts JC, Nguyen HO, Hayashi S, DeArmond SJ, Prusiner SB. Conformational transformation and selection of synthetic prion strains. Journal of Molecular Biology. 2011;413:527-542. DOI: 10.1016/j.jmb.2011.07.021
  78. 78. Baskakov IV. The many shades of prion strain adaptation. Prion. 2011;8:27836
  79. 79. Bian J, Khaychuk V, Angers RC, Fernandez-Borges N, Vidal E, Meyerett-Reid C, et al. Prion replication without host adaptation during interspecies transmissions. Proceedings of the National Academy of Sciences of the United States of America. 2017;114:1141-1146. DOI: 10.1073/pnas.1611891114
  80. 80. Ritchie DL, Boyle A, McConnell I, Head MW, Ironside JW, Bruce ME. Transmissions of variant Creutzfeldt-Jakob disease from brain and lymphoreticular tissue show uniform and conserved bovine spongiform encephalopathy-related phenotypic properties on primary and secondary passage in wild-type mice. Journal of General Virology. 2009;90:3075-3082. DOI: 10.1099/vir.0.013227-0
  81. 81. Aguzzi A, Heikenwalder M, Polymenidou M. Insights into prion strains and neurotoxicity. Nature Reviews. Molecular Cell Biology. 2007;8:552-561. DOI: 10.1038/nrm2204
  82. 82. Disease SC, Parchi P, Castellani R, Capellari S, Ghetti B, Young K, et al. Molecular basis of phenotypic variability in sporadic Creutzfeldt-Jakob disease. Annals of Neurology. 1996;39:767-778
  83. 83. Kretzschmar H, Tatzelt J. Prion disease: A tale of folds and strains. Brain Pathology (Zurich, Switzerland).2013;23:321-332. DOI: 10.1111/bpa.12045
  84. 84. Makarava N, Ostapchenko VG, Savtchenko R, Baskakov IV. Conformational switching within individual amyloid fibrils. The Journal of Biological Chemistry. 2009;284:14386-14395. DOI: 10.1074/jbc.M900533200
  85. 85. Candelise N, Schmitz M, Da Silva Correia SM, Arora AS, Villar-Piqué A, Zafar S, et al. Applications of the real-time quaking-induced conversion assay in diagnosis, prion strain-typing, drug pre-screening and other amyloidopathies. Expert Review of Molecular Diagnostics. 2017;17:897-904. DOI: 10.1080/14737159.2017.1368389
  86. 86. Magnusson K, Simon R, Sjölander D, Sigurdson CJ, Hammarström P, Nilsson KPR. Multimodal fluorescence microscopy of prion strain specific PrP deposits stained by thiophene-based amyloid ligands. Prion. 2014;8:319-329
  87. 87. Strains P, Phenomena TB. Prion strains and transmission barrier phenomena. Pathogens. 2018;7:5. DOI: 10.3390/pathogens7010005
  88. 88. Kim C, Haldiman T, Surewicz K, Cohen Y, Chen W, Blevins J, et al. Small protease sensitive oligomers of PrPSc in distinct human prions determine conversion rate of PrPC. PLoS pathogens. 2012;8:e1002835. DOI: 10.1371/journal.ppat.1002835
  89. 89. Peden AH, Sarode DP, Mulholland CR, Barria MA, Ritchie DL, Ironside JW, et al. The prion protein protease sensitivity, stability and seeding activity in variably protease sensitive prionopathy brain tissue suggests molecular overlaps with sporadic Creutzfeldt-Jakob disease. Acta Neuropathologica Communications. 2014;2:1-17. DOI: 10.1186/s40478-014-0152-4
  90. 90. Cohen ML, Kim C, Haldiman T, Elhag M, Mehndiratta P, Pichet T, et al. Rapidly progressive Alzheimer ’ s disease features distinct structures of amyloid-b. Brain. 2015;138:1009-1022. DOI: 10.1093/brain/awv006
  91. 91. Hartmann A, Muth C, Dabrowski O, Krasemann S, Glatzel M. Exosomes and the prion protein: More than one truth. Frontiers in Neuroscience. 2017;11:1-7. DOI: 10.3389/fnins.2017.00194
  92. 92. Zafar S, Shafiq M, Younas N, Schmitz M, Ferrer I, Zerr I. Prion protein interactome: Identifying novel targets in slowly and rapidly progressive forms of Alzheimer’s disease. Journal of Alzheimer's Disease. 2017;59:265-275. DOI: 10.3233/JAD-170237
  93. 93. Gambetti P, Kong Q, Zou W, Parchi P, Chen SG. Sporadic and familial CJD: Classification and characterisation. British Medical Bulletin. 2003;66:213-239. DOI: 10.1093/bmb/dg66.213

Written By

Saima Zafar, Neelam Younas, Mohsin Shafiq and Inga Zerr

Submitted: January 24th, 2018 Reviewed: August 3rd, 2018 Published: November 5th, 2018