Information

Are all animal species prone to cannibalism induced prion infection?


Humans have the tendency to get certain prion diseases when eating human flesh. It's known animals can get prion diseases as well.

Does cannibalism among other animal species also make them more susceptible to get a prion disease, and are there distinctions between mammals doing so and other orders like reptiles, birds, fish etc.?


It is perhaps worth looking into more historically established prion diseases in noncarnivorous animals, like sheep. If prion diseases were only transmitted by consuming prion-rich brain tissue, then they should be extremely rare (produced via unique misfolding events or mutations in affected individuals) or completely absent in wild herbivores and domestic herbivores which are not being fed meat meal.

In fact, I mention scrapie because it predates the practice of supplementing livestock feed with meat-derived protein. (The first documented mention of the disease dates back to about 1772 and mentions that the disease is about 40 years old at that point.) As it happens, the earliest mention of livestock feed or feed supplements being composed of meat and bone meal I can find dates to about 1890. Prion diseases also appear in wild populations of elk and deer in the form of Chronic Wasting Disease, currently a big problem in the northern US and Canada, as well as in cattle and sheep.

So how did scrapie come to be such a problem for European sheep farmers?

Well, for one thing, scrapie (and CWD) can be transmitted via ectoparasites. But the most common culprit probably lies in the soil. It turns out that infectious prions can survive for years in soil once they're deposited. Not only is the decomposition of a carcass a way to infect the soil with the misfolded prions, but CWD proteins are also present in the excreta of infected animals and even antler velvet.

This is a problem, because both scrapie and CWD can be acquired simply by consuming infected soil or grazing on grass containing it. This is most likely the most common way that these prion diseases are acquired naturally--not cannibalism at all, or at least not the sort we commonly think of! It's a simple fecal-oral route of transmission, albeit one with an alarmingly long potential incubation period.


An individual (animal or human) acquires a prion disease when they consume meat that contains prions (proteins that are mishapen enough to drastically change their functionality), which subsequently causes proteins within the individual to misfold into the same shape as the prion, resulting in a whole slew of problems.

As of right now, there is little knowledge of where prions come from/how they're formed. Also, there is little knowledge of how inter-species infections/transmissions occur. Researchers are currently investigating various combinations of inter-species transmissions, such as humans eating infected horse meat, or cats eating infected chicken meat, but still know only very little about this phenomenon.

To say which species have higher rates of prion disease when looking at a cannibalist communities within that species, I don't think we're anywhere near close to making those conclusions, and the same goes for inter-species transmissions.

All the best.


Behavior of Prions in the Environment: Implications for Prion Biology

Copyright: © 2013 Bartelt-Hunt, Bartz. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: This work was supported by the National Science Foundation, CBET-1149242, (S. Bartelt-Hunt) and the National Center for Research Resources, P20 RR0115635-6, C06 RR17417-01 and G200RR024001, (J. Bartz). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.


Subclinical prion infection

Prion diseases are transmissible neurodegenerative disorders that include scrapie in sheep, bovine spongiform encephalopathy (BSE) in cattle and Creutzfeldt–Jakob disease (CJD) in humans. The principal component of the infectious agent responsible for these diseases appears to be an abnormal isoform of the host-encoded prion protein (PrP), designated PrP Sc . Prion diseases are transmissible to the same or different mammalian species by inoculation with, or dietary exposure to, infected tissues. Although scrapie in sheep has been recognized for over 200 years, it is the recent epidemic of BSE that has centred much public and scientific attention on these neurodegenerative diseases. The occurrence of variant CJD in humans and the experimental confirmation that it is caused by the same prion strain as BSE has highlighted the need for intensive study into the pathogenesis of these diseases and new diagnostic and therapeutic approaches. The existence and implications of subclinical forms of prion disease are discussed.


Infectious particles, stress, and induced prion amyloids: a unifying perspective

Transmissible encephalopathies (TSEs) are believed by many to arise by spontaneous conversion of host prion protein (PrP) into an infectious amyloid (PrP-res, PrP (Sc) ) without nucleic acid. Many TSE agents reside in the environment, with infection controlled by public health measures. These include the disappearance of kuru with the cessation of ritual cannibalism, the dramatic reduction of epidemic bovine encephalopathy (BSE) by removal of contaminated feed, and the lack of endemic scrapie in geographically isolated Australian sheep with susceptible PrP genotypes. While prion protein modeling has engendered an intense focus on common types of protein misfolding and amyloid formation in diverse organisms and diseases, the biological characteristics of infectious TSE agents, and their recognition by the host as foreign entities, raises several fundamental new directions for fruitful investigation such as: (1) unrecognized microbial agents in the environmental metagenome that may cause latent neurodegenerative disease, (2) the evolutionary social and protective functions of different amyloid proteins in diverse organisms from bacteria to mammals, and (3) amyloid formation as a beneficial innate immune response to stress (infectious and non-infectious). This innate process however, once initiated, can become unstoppable in accelerated neuronal aging.

Keywords: Alzheimer disease Parkinson disease aging biofilms environmental pathogens latency metagenome nucleic acids transmissible encephalopathies yeast prions.

Figures

15 and 100 d. Gel load at 130 d was decreased to 0.5× for detection in the linear range. Log infectivity increase by ic route has been reproduced (n > 3 from different serial passages).

25 nm TSE viral particle binding its required host PrP…

25 nm TSE viral particle binding its required host PrP receptor to induce PrP-res amyloid. (A) Shows disintegration and elimination of the infectious particle with its nucleic acid core (solid circle) and protective protein capsid cage when there is no PrP on which to dock. (B) Shows two different PrP-res conformers induced by two different TSE viral strains (A and B particles with protective capsid cages). As previously modeled, the infectious particle initiates or “seeds” the PrP misfolding. As now shown experimentally, this amyloid can continue to perpetuate itself even after agent elimination. (C) Top depicts the manufacture of abundant TSE infectious particles with a residue of limited tightly bound PrP membrane attachment sites. Bottom shows late accumulating host PrP-res amyloid that can trap, protect, and eventually eliminate agent.


Sephin1 Reduces Prion Infection in Prion-Infected Cells and Animal Model

Prion diseases are fatal infectious neurodegenerative disorders in human and animals caused by misfolding of the cellular prion protein (PrP C ) into the infectious isoform PrP Sc . These diseases have the potential to transmit within or between species, and no cure is available to date. Targeting the unfolded protein response (UPR) as an anti-prion therapeutic approach has been widely reported for prion diseases. Here, we describe the anti-prion effect of the chemical compound Sephin1 which has been shown to protect in mouse models of protein misfolding diseases including amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) by selectively inhibiting the stress-induced regulatory subunit of protein phosphatase 1, thus prolonging eIF2α phosphorylation. We show here that Sephin1 dose and time dependently reduced PrP Sc in different neuronal cell lines which were persistently infected with various prion strains. In addition, prion seeding activity was reduced in Sephin1-treated cells. Importantly, we found that Sephin1 significantly overcame the endoplasmic reticulum (ER) stress induced in treated cells, as measured by lower expression of stress-induced aberrant prion protein. In a mouse model of prion infection, intraperitoneal treatment with Sephin1 significantly prolonged survival of prion-infected mice. When combining Sephin1 with the neuroprotective drug metformin, the survival of prion-infected mice was also prolonged. These results suggest that Sephin1 could be a potential anti-prion drug selectively targeting one component of the UPR pathway.

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IMMUNOINTERVENTION TARGETED AT PrP

The striking blindness of the immune system to TSE agents [77] is not a result of the fact that the host is immunosuppressed as a consequence of infection, nor is it caused by a lack of intrinsic immunogenicity of PrP Sc , the main component of prions. Indeed, PrP from a foreign species or autologous PrP injected into Prnp knockout mice evokes good antibody responses [787980]. Blindness is simply a result of self-tolerance, of the fact that the PrP is not perceived as foreign or as “dangerous” and thus does not alert the immune system. Even the fact that PrP Sc represents a different folding that has not been seen by the immune system before infection does not provide sufficient difference from the normal configuration to evoke a response. The immune system takes only into account the primary sequence of the protein and the peptidic fragments that result from the processing of PrP C and PrP Sc . The two sets of epitopes that are sampled by MHC molecules seem to be fundamentally similar, despite the fact that both conformers have different physicochemical properties and most importantly, different sensitivities to proteolytic enzymes and probably to endopeptidases. It will be interesting to find out whether minor differences in peptidic motifs exist nevertheless and could serve as a basis for generating T cell responses specific for PrP Sc only.

Although self-tolerance to PrP remains a real obstacle to vaccination attempts, several groups have nervertheless started to evaluate, through in vitro models or by using transgenic mice, the potential benefits of an immune response.

A first encouraging indication has come from two recently published studies showing that anti-PrP antibodies added to the culture medium could cure infected cell lines by preventing the conversion of PrP C into PrP Sc [81, 82]. In both studies, the lines or clones were derived from N2a, a murine neuroblastoma of A/J strain origin, which constitutively expresses PrP C and can be infected with relative ease by coculture with infectious brain extracts from scrapie mice. Infected N2a cells can continuously produce PK-resistant PrP Sc and remain infectious for mice even after multiple in vitro passages [83]. They are excellent models for studying the cellular and molecular events involved in PrP conversion and for screening potential inhibitors of the reaction [84].

The monoclonal antibodies (mAb) that prevent in vitro cellular conversion of PrP C into PrP Sc are not specific for one particular isoform, as they bind equally to both. Conversely, not every anti-PrP antibody has the capacity to block conversion with the same efficacy. As shown in both studies, the binding to a region of the PrP molecule between residues 132 and 156, corresponding to the first α helix of PrP C , appears to be critical. How these antibodies inhibit conversion is still not totally understood. They could possibly hinder physical contact between the two conformers or prevent the docking of an auxiliary cofactor catalyzing transconformation. Alternatively, it is possible that the antibodies redirect PrP C traffic and sequester the protein in a subcellular compartment where conversion cannot take place, as it is inaccessible to PrP Sc , or the particular physicochemical conditions do not favor conversion. Finally, a less exciting explanation with doubtful in vivo relevance might be that antibodies enhance selective pressure against infected cells and let uninfected cells over-grow.

The question of whether antibodies can also prevent conversion in vivo has actually been addressed recently [85]. The authors have produced a transgenic mouse expressing the rearranged VH domain of anti-PrP antibody 6H4, one of the mAb that blocks conversion in vitro. The transgenic line develops a B cell repertoire that is heterogeneous because of the free endogenous rearrangements of κ and λ light chains but is still biased toward PrP specificities as a result of the constraint imposed by the rearranged 6H4 heavy chain. 6H4 μ-Chain transgenic mice produce spontaneous anti-PrP antibodies of immunoglobulin M isotype, reactive in enzyme-linked immunosorbent assay, and Western blot assays. PrP Sc replication and scrapie infectivity have been followed in tissues of these mice after i.p. inoculation of RML prions. Compared with wild-type mice, replication of prions is significantly delayed in the 6H4 μ-chain transgenics. There is also considerably less accumulation of PrP Sc in the spleen and in the brain. Thus, endogenously produced anti-PrP antibodies can inhibit scrapie progression in vivo. However, the report does not mention whether clinical disease is effectively delayed and if so, for how long. Although the mechanisms of inhibition remain to be clarified, the results are encouraging, as they suggest first, that antibodies can antagonize prion conversion in vivo second, that B cell clones directed at self-PrP are not necessarily doomed to clonal deletion or peripheral anergy and third, that anti-PrP autoantibodies do not cause apparent manifestations of autoimmunity. This latter issue must be considered with a certain degree of caution after the report of Souan et al. [86] showing that Lewis rats immunized with immunogenic peptides from homologous PrP may develop severe skin inflammation.

Cell-mediated immunity against PrP has by far not been as intensively explored as humoral immunity. Yet, there are good reasons to believe that T cells recognize processed epitopes of PrP C or PrP Sc , as anti-PrP antibodies produced under heterologous conditions or in Prnp°/° mice are subject to isotypic switching, an event that requires the cooperation of antigen-specific helper T cells. Souan et al. [86, 87] have addressed the question of the T cell-mediated response against PrP in two recent studies. In the more detailed study, the authors have immunized normal wild-type mice of three independent strains, NOD, C57BL/6, and A/J, with a library of synthetic peptides covering almost the entire sequence of mouse PrP. After a few cycles of in vitro stimulation with peptides and antigen-presenting cells (APC), they were able to indentify two epitopic motifs that recall CD4 + T cells in the three strains of mice, despite their different MHC haplotypes. One peptide spans from residue 131 to 150, the very same region that is critical in the blocking of PrP conversion by antibodies the other is at the C-terminus between residues 211 and 230. Finally, the authors show that in compatible A/J mice, which have been immunized with immunogenic PrP peptides and have received a transplant of N2a-infected cells, the amount of PrP Sc recovered from the growing tumors is significantly lower than in tumors growing in naive controls. Thus, an ongoing anti-PrP immune response seems able to antagonize the in vivo conversion of PrP. Like the report by Aguzzi and co-workers [85], this study is encouraging in several respects. It suggests that, although rather indirectly, anti-PrP immunity might slow down PrP conversion and that T cell tolerance can be overcome in normal mice by active immunization with synthetic peptides with no adverse manifestation of autoimmunity. However, several questions remain to be answered: the effect of peptide immunization on the natural disease and the respective contributions of cell-mediated and humoral immunity, as antibodies are produced concomitantly by B cells as a consequence of helper T cell activation. Starting from experiments made in Prnp knockout mice not tolerant to PrP, our own observations confirm that PrP is normally processed and presented to T cells by APC and that T cell lines can be generated against a few dominant epitopes residing in the same region-spaning residues, 142 and 186. However, at variance with the results of Souan et al. [87], we found that wild-type C57/B6 mice are rather refractory to immunization with PrP peptides. Relatively few clones emerge from in vitro cultures and require numerous iterative cycles of restimulation in the presence of antigen and interleukin-2. Some epitopes are the same as those identified with T cells from Prnp knockout mice others are not, suggesting that the T cell repertoires in mice expressing or not expressing PrP are not totally overlapping. We anticipate that, on the basis of our results, breaking tolerance in normal individuals will probably require sophisticated strategies similar to those used for immunization against poorly immunogenic tumors. Tumor immunology has pionneered in this field using strategies based on strong bacterial adjuvants, modified peptides, antigen-loaded DCs, and T cell clones redirected by transfection of high-affinity TCRs. Similar strategies will probably have to be developed for breaking tolerance and antagonizing prion propagation in infected hosts.


Results

Challenge of CD-1 Mice with Sc237 Syrian Hamster Prions.

Conventional CD-1 mice were intracerebrally inoculated with ≈ 8.5 × 10 6 LD50 units of Sc237 prions or vehicle (PBS) alone. No scrapie-like clinical signs were observed in any animals from either group. All mice were carefully observed until death or until they developed other, intercurrent disease, which necessitated culling according to normal animal care criteria (Table 1). The observation periods for the Sc237- and PBS-inoculated mice [638 ± 28 days and 649 ± 48 days (means ± SEM), respectively] were not significantly different (P = 0.84, unpaired t test).

Challenge of CD-1 mice with Sc237 Syrian hamster prions (38)

Western blot analysis was performed on all brains. PrP Sc was demonstrated in approximately 50% of the Sc237-inoculated mice, but none of the PBS-inoculated controls. The observation periods for the PrP Sc -positive mice ranged from 659 to 828 days postinoculation, whereas PrP Sc -negative Sc327-inoculated mice were observed for 408–655 days. The differences in mean observation periods for PrP Sc -positive and PrP Sc -negative Sc237-inoculated mice were statistically significant (727 ± 15 and 528 ± 30 days, respectively P < 0.0001, unpaired t test). Western blotting was performed both with mAb 3F4, which detects hamster but not mouse PrP (23), and polyclonal antibody R073, which detects both hamster and mouse PrP (26) to determine the type of PrP Sc present. Mouse PrP Sc was readily detectable, but no hamster PrP Sc could be detected (Fig. 1).

Western blot analysis of brain homogenates treated with proteinase K using anti-PrP antibodies R073, which detects both mouse and hamster PrP (lanes 1–3) and 3F4, which detects hamster PrP only (lanes 4–6) (40). Lanes 1 and 4: Sc237-inoculated hamster lanes 2 and 5: Sc237-inoculated CD-1 mouse positive for murine PrP Sc lanes 3 and 6: Sc237-inoculated mouse negative for PrP Sc . Numbers adjacent to horizontal lines indicate positions of molecular mass markers (kDa). Ten microliters of a 10% brain homogenate was loaded in each lane.

Mice from each group were subjected to full neuropathological examination. Several Sc237-inoculated mice showed the histological features of spongiform encephalopathy with PrP amyloid plaques, consistent with typical prion disease (Fig. 2). Age-matched, PBS-inoculated controls, which died at a similar time postinoculation, all had normal histology and negative PrP immunohistochemistry.

Neuropathological examination of Sc237-inoculated (a) and (b) and PBS-inoculated (c) and (d) CD-1 mice (41). (a and c) Hematoxylin- and eosin-stained sections showing spongiform neurodegeneration in a. (b and d) PrP immunohistochemistry showing abnormal PrP immunoreactivity including PrP-positive plaques in b. (c and d) Normal appearances. Magnifications: ×150.

Passage of Brain Homogenate from Sc237- or Mock-Inoculated CD-1 Mice in Both Mice and Hamsters.

To investigate whether prion propagation had occurred in Sc237-inoculated mice and to study the characteristics of any infectious prions detected, we performed second-passage transmissions into CD-1 mice, Tg20 mice, which overexpress wild-type mouse PrP and have shortened incubation periods for mouse prions (27), and Syrian hamsters. Two Sc237-inoculated CD-1 mice were chosen for passage, one was PrP Sc positive, the other negative. Two PBS-inoculated CD-1 mice were passaged as a negative control.

All animals in all three groups (CD-1 and Tg20 mice and Syrian hamsters) inoculated with the Sc237-inoculated PrP Sc -positive CD-1 mouse brain developed typical scrapie signs with incubation periods as shown in Table 2.

Passage of infectivity from Sc237- or PBS-inoculated CD-1 mice into both mice and hamsters (38)

Inoculation from an Sc237-inoculated PrP Sc -negative CD-1 mouse into the three types of animal resulted in transmission only to hamsters with very prolonged and more variable incubation periods (148–238 days) (Table 2). None of the animals inoculated with material from the PBS-inoculated CD-1 mice had shown any scrapie-like symptoms at up to 650 days postinoculation.

All animals from these passage groups were examined by Western blotting and/or neuropathology. All clinically affected animals demonstrated classical neuropathological features of prion disease with widespread spongiform vacuolation and positive PrP immunoreactivity (data not shown). Western blotting revealed the presence of protease-resistant PrP Sc (Fig. 3).

Western blot analysis of proteinase K-treated brain homogenates using anti-PrP antibody R073 to determine PrP Sc types (40). Lane 1: Sc237-inoculated Syrian hamster lane 2: Sc237-inoculated CD-1 mouse lanes 3–5: passage of Sc237-inoculated CD-1 mouse into Syrian hamster (lane 3), CD-1 mouse (lane 4), and Tg20 mouse (lane 5). Numbers adjacent to horizontal lines indicate positions of molecular mass markers (kDa).

End-Point Titration of CD-1-Passaged Sc237 Prions.

The prion titer in CD-1 mice inoculated with Sc237 hamster prions was determined by end-point titration, both in Tg20 mice and Syrian hamsters (Table 3). Prion titers in Sc237-inoculated PrP Sc -positive brain were estimated at ≈10 8 LD50/g in hamsters and ≈10 7 LD50/g in Tg20 mice. Titration of prions from Sc237-inoculated PrP Sc -negative CD-1 mouse brain revealed a titer of ≈10 6 LD50/g in hamsters but there was no transmission to Tg20 mice.

End-point titration of Sc237-inoculated CD-1 mice in Syrian hamsters and Tg20 mice (39)

Molecular Analysis of Strain Characteristics of CD-1 Mouse Passaged Sc237 Prions.

Prion strains can be differentiated by differences in PrP Sc fragment sizes and glycoform ratios on Western blots after proteinase K cleavage. We compared PrP Sc in hamsters inoculated with Sc237 prions with that seen in Sc237-inoculated CD-1 mice and in brains of hamsters and mice inoculated with Sc237-inoculated PrP Sc -positive and PrP Sc -negative CD-1 mice (Fig. 3). The PrP Sc type seen in Sc237-inoculated CD-1 mice differed sharply from that in Sc-237-inoculated hamsters, both with respect to fragment sizes and glycoform ratios after proteinase K digestion. Size of unglycosylated PrP fragment was 21.7 kDa in Sc237-inoculated CD-1 mice, and the most abundant glycoform was monoglycosylated [ratios (mean ± SEM): 34.6 ± 1.6% di- 45.3 ± 1.6% mono-, and 20.0 ± 0.4% unglycosylated PrP]. In Sc237-inoculated hamsters, diglycosylated PrP predominated (ratios: 83.0% di- 15.2% mono-, and 1.8% unglycosylated PrP), and the unglycosylated fragment was approximately 20.7 kDa.

On passage of prions from Sc237-inoculated CD-1 mice to additional CD-1 mice, and also to Tg20 mice, the same PrP Sc type was generated, with fragment sizes and glycoform ratios indistinguishable from those in the Sc-237-inoculated CD-1 mice. However, on passage in Syrian hamsters, the PrP Sc type reverted to that seen in Sc237-inoculated hamsters (Fig. 3).


Contents

Known spongiform encephalopathies
ICTVdb Code Disease name Natural host Prion name PrP isoform Ruminant
Non-human mammals
90.001.0.01.001. Scrapie Sheep and goats Scrapie prion PrP Sc Yes
90.001.0.01.002. Transmissible mink encephalopathy (TME) Mink TME prion PrP TME No
90.001.0.01.003. Chronic wasting disease (CWD) Elk, white-tailed deer, mule deer and red deer CWD prion PrP CWD Yes
90.001.0.01.004. Bovine spongiform encephalopathy (BSE)
commonly known as "Mad Cow Disease"
Cattle BSE prion PrP BSE Yes
90.001.0.01.005. Feline spongiform encephalopathy (FSE) Cats FSE prion PrP FSE No
90.001.0.01.006. Exotic ungulate encephalopathy (EUE) Nyala and greater kudu EUE prion PrP EUE Yes
Camel spongiform encephalopathy (CSE) [8] Camel PrP CSE Yes
Human diseases
90.001.0.01.007. Kuru Humans Kuru prion PrP Kuru No
90.001.0.01.008. Creutzfeldt–Jakob disease (CJD) CJD prion PrP sCJD No
Variant Creutzfeldt–Jakob disease (vCJD, nvCJD) vCJD prion [9] PrP vCJD
90.001.0.01.009. Gerstmann-Sträussler-Scheinker syndrome (GSS) GSS prion PrP GSS No
90.001.0.01.010. Fatal familial insomnia (FFI) FFI prion PrP FFI No
Familial spongiform encephalopathy [10]

The degenerative tissue damage caused by human prion diseases (CJD, GSS, and kuru) is characterised by four features: spongiform change, neuronal loss, astrocytosis, and amyloid plaque formation. These features are shared with prion diseases in animals, and the recognition of these similarities prompted the first attempts to transmit a human prion disease (kuru) to a primate in 1966, followed by CJD in 1968 and GSS in 1981. These neuropathological features have formed the basis of the histological diagnosis of human prion diseases for many years, although it was recognized that these changes are enormously variable both from case to case and within the central nervous system in individual cases. [11]

The clinical signs in humans vary, but commonly include personality changes, psychiatric problems such as depression, lack of coordination, and/or an unsteady gait (ataxia). Patients also may experience involuntary jerking movements called myoclonus, unusual sensations, insomnia, confusion, or memory problems. In the later stages of the disease, patients have severe mental impairment (dementia) and lose the ability to move or speak. [12]

Early neuropathological reports on human prion diseases suffered from a confusion of nomenclature, in which the significance of the diagnostic feature of spongiform change was occasionally overlooked. The subsequent demonstration that human prion diseases were transmissible reinforced the importance of spongiform change as a diagnostic feature, reflected in the use of the term "spongiform encephalopathy" for this group of disorders.

Prions appear to be most infectious when in direct contact with affected tissues. For example, Creutzfeldt–Jakob disease has been transmitted to patients taking injections of growth hormone harvested from human pituitary glands, from cadaver dura allografts and from instruments used for brain surgery (Brown, 2000) (prions can survive the "autoclave" sterilization process used for most surgical instruments). It is also believed [ by whom? ] that dietary consumption of affected animals can cause prions to accumulate slowly, especially when cannibalism or similar practices allow the proteins to accumulate over more than one generation. An example is kuru, which reached epidemic proportions in the mid-20th century in the Fore people of Papua New Guinea, who used to consume their dead as a funerary ritual. [13] Laws in developed countries now ban the use of rendered ruminant proteins in ruminant feed as a precaution against the spread of prion infection in cattle and other ruminants.

There exists evidence that prion diseases may be transmissible by the airborne route. [14]

Note that not all encephalopathies are caused by prions, as in the cases of PML (caused by the JC virus), CADASIL (caused by abnormal NOTCH3 protein activity), and Krabbe disease (caused by a deficiency of the enzyme galactosylceramidase). Progressive Spongiform Leukoencephalopathy (PSL)—which is a spongiform encephalopathy—is also probably not caused by a prion, although the adulterant that causes it among heroin smokers has not yet been identified. [15] [16] [17] [18] This, combined with the highly variable nature of prion disease pathology, is why a prion disease cannot be diagnosed based solely on a patient's symptoms.

Genetics

Mutations in the PRNP gene cause prion disease. Familial forms of prion disease are caused by inherited mutations in the PRNP gene. Only a small percentage of all cases of prion disease run in families, however. Most cases of prion disease are sporadic, which means they occur in people without any known risk factors or gene mutations. In rare circumstances, prion diseases also can be transmitted by exposure to prion-contaminated tissues or other biological materials obtained from individuals with prion disease.

The PRNP gene provides the instructions to make a protein called the prion protein (PrP). Under normal circumstances, this protein may be involved in transporting copper into cells. It may also be involved in protecting brain cells and helping them communicate. 24 [ citation needed ] Point-Mutations in this gene cause cells to produce an abnormal form of the prion protein, known as PrP Sc . This abnormal protein builds up in the brain and destroys nerve cells, resulting in the signs and symptoms of prion disease.

Familial forms of prion disease are inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. In most cases, an affected person inherits the altered gene from one affected parent.

In some people, familial forms of prion disease are caused by a new mutation in the PRNP gene. Although such people most likely do not have an affected parent, they can pass the genetic change to their children.

Protein-only hypothesis

Protein could be the infectious agent, inducing its own replication by causing conformational change of normal cellular PrP C into PrP Sc . Evidence for this hypothesis:

  • Infectivity titre correlates with PrP Sc levels. However, this is disputed. [19]
  • PrP Sc is an isomer of PrP C
  • Denaturing PrP removes infectivity [20]
  • PrP-null mice cannot be infected [21]
  • PrP C depletion in the neural system of mice with established neuroinvasive prion infection reverses early spongeosis and behavioural deficits, halts further disease progression and increases life-span [22]

Multi-component hypothesis

While not containing a nucleic acid genome, prions may be composed of more than just a protein. Purified PrP C appears unable to convert to the infectious PrP Sc form, unless other components are added, such as RNA and lipids. [23] These other components, termed cofactors, may form part of the infectious prion, or they may serve as catalysts for the replication of a protein-only prion.

Spiroplasma hypothesis

There is some disputed evidence for the role of bacteria of the Spiroplasma genus in the etiology of TSEs, primarily due to the work of Frank Bastian. The fact that PrP Sc cannot be detected in about 10% of cases of CWD, while Bastian claims to have successfully cultured Spiroplasma spp. from the brains of 100% of deer with CWD and sheep with scrapie, which were able to spread the disease to other ruminants in the absence of PrP Sc , [24] has led him and others to suspect that Spiroplasma infection may be the genuine cause of TSEs. Under this hypothesis PrP Sc would merely be an imperfect marker of infection (with both sensitivity and NPV <1) either induced by Spiroplasma directly or by a defence mechanism of the host.

Other researchers have found no evidence for the Spiroplasma hypothesis of TSE causation. [25] [26] Bastian however attributes the inability to find Spiroplasma in 100% of cases to genetic variability. [27] Bastian also stated that the authors of the hamster study used different primers for their PCR than he did, which could result in a false negative.

Viral hypothesis

This hypothesis postulates that an as of yet undiscovered infectious viral agent is the cause of the disease. Evidence for this hypothesis is as follows:

  • Incubation time is comparable to a lentivirus
  • Strain variation of different isolates of PrP Sc [28]
  • An increasing titre of PrP Sc as the disease progresses suggests a replicating agent.

There continues to be a very practical problem with diagnosis of prion diseases, including BSE and CJD. They have an incubation period of months to decades during which there are no symptoms, even though the pathway of converting the normal brain PrP protein into the toxic, disease-related PrP Sc form has started. At present, there is virtually no way to detect PrP Sc reliably except by examining the brain using neuropathological and immunohistochemical methods after death. Accumulation of the abnormally folded PrP Sc form of the PrP protein is a characteristic of the disease, but it is present at very low levels in easily accessible body fluids like blood or urine. Researchers have tried to develop methods to measure PrP Sc , but there are still no fully accepted methods for use in materials such as blood.

In 2010, a team from New York described detection of PrP Sc even when initially present at only one part in a hundred billion (10 −11 ) in brain tissue. The method combines amplification with a novel technology called Surround Optical Fiber Immunoassay (SOFIA) and some specific antibodies against PrP Sc . After amplifying and then concentrating any PrP Sc , the samples are labelled with a fluorescent dye using an antibody for specificity and then finally loaded into a micro-capillary tube. This tube is placed in a specially constructed apparatus so that it is totally surrounded by optical fibres to capture all light emitted once the dye is excited using a laser. The technique allowed detection of PrP Sc after many fewer cycles of conversion than others have achieved, substantially reducing the possibility of artefacts, as well as speeding up the assay. The researchers also tested their method on blood samples from apparently healthy sheep that went on to develop scrapie. The animals’ brains were analysed once any symptoms became apparent. The researchers could therefore compare results from brain tissue and blood taken once the animals exhibited symptoms of the diseases, with blood obtained earlier in the animals’ lives, and from uninfected animals. The results showed very clearly that PrP Sc could be detected in the blood of animals long before the symptoms appeared. [29] [30]

Transmissible spongiform encephalopathies (TSE) are very rare but can reach epidemic proportions. [ clarification needed ] It is very hard to map the spread of the disease due to the difficulty of identifying individual strains of the prions. This means that, if animals at one farm begin to show the disease after an outbreak on a nearby farm, it is very difficult to determine whether it is the same strain affecting both herds—suggesting transmission—or if the second outbreak came from a completely different source.

Classic Creutzfeldt-Jakob disease (CJD) was discovered in 1920. It occurs sporadically over the world but is very rare. It affects about one person per million each year. Typically, the cause is unknown for these cases. It has been found to be passed on genetically in some cases. 250 patients contracted the disease through iatrogenic transmission (from use of contaminated surgical equipment). [31] This was before equipment sterilization was required in 1976, and there have been no other iatrogenic cases since then. In order to prevent the spread of infection, the World Health Organization created a guide to tell health care workers what to do when CJD appears and how to dispose of contaminated equipment. [32] The Centers for Disease Control and Prevention (CDC) have been keeping surveillance on CJD cases, particularly by looking at death certificate information. [33]

Chronic wasting disease (CWD) is a prion disease found in North America in deer and elk. The first case was identified as a fatal wasting syndrome in the 1960s. It was then recognized as a transmissible spongiform encephalopathy in 1978. Surveillance studies showed the endemic of CWD in free-ranging deer and elk spread in northeastern Colorado, southeastern Wyoming and western Nebraska. It was also discovered that CWD may have been present in a proportion of free-ranging animals decades before the initial recognition. In the United States, the discovery of CWD raised concerns about the transmission of this prion disease to humans. Many apparent cases of CJD were suspected transmission of CWD, however the evidence was lacking and not convincing. [34]

In the 1980s and 1990s, bovine spongiform encephalopathy (BSE or "mad cow disease") spread in cattle at an epidemic rate. The total estimated number of cattle infected was approximately 750,000 between 1980 and 1996. This occurred because the cattle were fed processed remains of other cattle. Then human consumption of these infected cattle caused an outbreak of the human form CJD. There was a dramatic decline in BSE when feeding bans were put in place. On May 20, 2003, the first case of BSE was confirmed in North America. The source could not be clearly identified, but researchers suspect it came from imported BSE-infected cow meat. In the United States, the USDA created safeguards to minimize the risk of BSE exposure to humans. [35]

Variant Creutzfeldt-Jakob disease (vCJD) was discovered in 1996 in England. There is strong evidence to suggest that vCJD was caused by the same prion as bovine spongiform encephalopathy. [36] A total of 231 cases of vCJD have been reported since it was first discovered. These cases have been found in a total of 12 countries with 178 in the United Kingdom, 27 in France, five in Spain, four in Ireland, four in the United States, three in the Netherlands, three in Italy, two in Portugal, two in Canada, and one each in Japan, Saudi Arabia, and Taiwan. [37]

In the 5th century BCE, Hippocrates described a disease like TSE in cattle and sheep, which he believed also occurred in man. [38] Publius Flavius Vegetius Renatus records cases of a disease with similar characteristics in the 4th and 5th centuries AD. [39] In 1755, an outbreak of scrapie was discussed in the British House of Commons and may have been present in Britain for some time before that. [40] Although there were unsupported claims in 1759 that the disease was contagious, in general it was thought to be due to inbreeding and countermeasures appeared to be successful. Early-20th-century experiments failed to show transmission of scrapie between animals, until extraordinary measures were taken such as the intra-ocular injection of infected nervous tissue. No direct link between scrapie and disease in man was suspected then or has been found since. TSE was first described in man by Alfons Maria Jakob in the 1921. [41] Daniel Carleton Gajdusek's discovery that Kuru was transmitted by cannibalism accompanied by the finding of scrapie-like lesions in the brains of Kuru victims strongly suggested an infectious basis to TSE. [42] A paradigm shift to a non-nucleic infectious entity was required when the results were validated with an explanation of how a prion protein might transmit spongiform encephalopathy. [43] Not until 1988 was the neuropathology of spongiform encephalopathy properly described in cows. [44] The alarming amplification of BSE in the British cattle herd heightened fear of transmission to humans and reinforced the belief in the infectious nature of TSE. This was confirmed with the identification of a Kuru-like disease, called new variant Creutzfeldt–Jakob disease, in humans exposed to BSE. [45] Although the infectious disease model of TSE has been questioned in favour of a prion transplantation model that explains why cannibalism favours transmission, [46] the search for a viral agent is being continued in some laboratories. [47] [48]


Prions: Diseases and Treatment

Prions comprise a distinctive class of infectious agents that are protein-based and lack a specific nucleic acid genome. The prion concept includes novel protein-based elements of inheritance, that is, altered forms of host proteins that, when transferred to a new host, can cause a heritable phenotypic change in the recipient. Most prions are pathogens but, compared to all other pathogens (e.g., viruses, bacteria, fungi, parasites), prions are unique in that they propagate within and between hosts without carrying or replicating any DNA or RNA genes of their own.

Prions are typically refolded and aggregated proteins that propagate themselves by incorporating and inducing the refolding of the corresponding normal form of the protein in the host. The prion aggregate grows and then is fragmented somehow to generate more prion aggregates. In many ways, like Kurt Vonnegut’s “Ice Nine”, the growth of prions is analogous to the templated growth of crystals, and prions are often described as “seeds” by analogy to seed crystals. Thus, prions need not carry any nucleic acid code for themselves, but a susceptible host must make the normal precursor protein from which the infectious prions are made. Many, if not most, proteins can refold and/or assemble into ordered aggregates that can seed further growth under certain natural or experimental conditions, whether in a tissue or a test tube. However, not all such protein aggregates are infectious prions. The term prion implies that at the biological level the refolded state of the protein can propagate between hosts, or at least from cell-to-cell within a multicellular host. There have been recent calls to include all protein states that promote their own growth as multimeric assemblies under the prion umbrella, but this broadened usage of the term neglects the core concept of transmissibility and fails to discriminate prions from many cellular structures that can grow but have no tendency to spread to other cells and individuals.

History of Research

The prototypic prion disease was a deadly and mysterious transmissible neurodegenerative disease of sheep called scrapie. Early studies revealed that the scrapie agent was unusually resistant to treatments that disinfect other pathogens and could lay dormant in pastures for years. The scrapie agent’s resistance to radiation, in particular, led to proposals in the 1960’s by J.S. Griffith and Tikva Alper that it represents a novel class of pathogen that lacks its own nucleic acid genome and might instead be an abnormal self-replicating form of a protein or membrane. Meanwhile, Carlton Gajdusek’s descriptions of the brain pathology of the human disease kuru in Papua New Guinea led William Hadlow to the observation that kuru looks like scrapie in sheep. Accordingly, Hadlow recommended that kuru be tested for transmissibility from humans to other primates. Gajdusek did so successfully, and showed that the Fore people were acquiring kuru during ritual cannibalistic feasts. A striking feature of kuru and other prion diseases that has often obscured their causes is the long incubation periods between the initial infection and the appearance of clinical signs, which, in humans, can exceed four decades.

Lymph nodes from (a) healthy and (b) infected sheep – colouring with antibodies shows clear sign of scrapie prions in the tissue of the infected sheep / wikipedia.org

In the 1980’s Stanley Prusiner coined the term prion for such agents and first identified the specific host protein (prion protein or PrP) that is the main component of scrapie prions. Homologs of the same protein were then found in many mammalian species, including humans, and, abnormal PrP aggregates were found in other transmissible scrapie-like neurodegenerative diseases of humans and animals. These diseases are now known as prion diseases or transmissible spongiform encephalopathies. Prusiner, Charles Weissmann and others showed that PrP is an essential susceptibility factor for prion diseases.

Although the word prion was first applied to the transmissible spongiform encephalopathies described above, the first unequivocal evidence that infectious proteins exist in biology came from Reed Wickner’s realization in 1994 that certain unexplained epigenetic elements of yeast were prions. These prions were not composed of a PrP homolog, but of entirely distinct proteins of yeast. The relative simplicity and power of yeast biology and genetics enabled Wickner and others to clearly demonstrate a number of fundamental principles of prion biology and structure that have been much more difficult to pin down with mammalian prion models.

Methods of Research

Unfortunately, many of the standard methods that have long been crucial in studies of conventional pathogens –pathogen-specific genetics, serology, x-ray crystallography, nuclear magnetic resonance (NMR) spectroscopy — have been exceptionally difficult to apply to prions. Without any pathogen-specific genes to sequence and mutate, many of the standard genetic and reverse genetic approaches to revealing pathogen structure and function have not been available. Because prions are composed of host (self) proteins, there is little host immune response to the pathogen, and no easy serological, antibody-based way to detect prion infections. Because mammalian prions tend to be tightly packed, heavily glycosylated, and bound to other host molecules, even prion-specific conformational epitopes (surfaces recognized by antibodies) on the PrP aggregates have been difficult to find and exploit. The aggregated, yet non-crystalline, nature of purified prions has long stymied attempts to determine their 3-D structures.

For many years the only way to detect and measure mammalian prions was by bioassay in animals, which, even in the fastest rodent models, takes months to years for a single experiment. Prion strains were typically discriminated in a given host by comparing incubation periods, neuropathological patterns, and biochemical attributes of the disease-associated PrP deposits or prions.
Fortunately, more recently, powerful cell-free prion amplification assays such as protein misfolding cyclic amplification (PMCA), real-time quaking induced conversion (RT-QuIC) and the scrapie cell assay have been developed that exploit the inherent replication mechanism of prions. PMCA and RT-QuIC are extraordinarily sensitive and can amplify the presence of prions by a trillion-fold, almost to the point of detecting a few prion particles. PMCA reactions faithfully propagate prion infectivity, reflecting and illuminating many aspects of prion biology. RT-QuIC assays do not, as a rule, propagate fully infectious prions, but provide faster, more practical, higher-throughput methods for detecting prions. As such, they have become the state-of-the-art in diagnosing prion diseases. Both PMCA and RT-QuIC can, in some cases, discriminate important prion strains within given host species.

Slow progress is being made in revealing the underlying structure of prions. Solid state NMR studies have revealed molecular architectures of some fungal prions and prion-like fibrillar structures of mammalian PrP. Electron crystallography, fiber diffraction and cryo-electron microscopic studies have also provided key structural constraints for mammalian prions, but further improvements in the application of these and potentially other structural biological methods are sorely needed.

Structure and Reproduction of Prions

It has been extremely challenging to unravel the structures and replication mechanisms of mammalian prions at least in molecular detail. One must first explain how misfolded host proteins can propagate as pathogens without carrying any of their own nucleic acid-based genetic code. Then one must also explain how proteins of a single amino acid sequence, such as that of PrP in a given host animal, can form different strains of prions that propagate faithfully and cause distinct disease phenotypes –without requiring the sorts of genetic mutations that explain strain variation in conventional pathogens.

Beyond that gross description, the details of prion structure and propagation at the molecular level remain obscure. Also unresolved is how prions propagate beyond the original site of infection in the host. Current evidence suggests that the most efficient transfer between cells involves membranous structures such as exosomes or tunneling nanotubes, most likely because prions are usually bound to membranes by lipid anchors however, the relevance of these membranous structures to prion spreading in vivo remains to be determined. Spreading mechanisms are important to understand because the relative abilities of various misfolded self-propagating protein aggregates to spread within and between cells, tissues and individuals are primary determinants of whether they act as infectious pathogens or relatively innocuous accidents of protein metabolism.

Prion Diseases

Many, but not all, mammalian species are susceptible to PrP-based prion diseases, including humans, non-human primates, cattle, sheep, goats, deer, elk, moose, cats, mink, rodents and various exotic ungulates. Dogs and horses appear to be notable exceptions. Different species usually express slightly different normal PrP molecules, and their differences in PrP amino acid sequence can strongly influence host susceptibility to incoming prion infections. For example, humans are known to be somewhat susceptible to bovine spongiform encephalopathy (BSE), but appear to be resistant to sheep scrapie and, as far as we know, chronic wasting disease in cervids. For some reason, bank voles and squirrel monkeys are unusually susceptible to a wide range of prion infections from other species.

The mechanisms by which prion infections cause neurodegenerative disease are unclear. Different prion strains within a given host type can accumulate preferentially in different regions of the central nervous system and cause a range of neuropathological lesions. Obviously, the ultimate effect of at least some of the damage is the malfunctioning and loss of neurons, causing a variety of clinical signs and death. A number of neurophysiological processes and pathways are known to be disrupted, but much remains to be determined about (i) whether such disruptions are due to direct or indirect toxicities of prions, and (ii) the extent to which any given deficit or combination of deficits is most responsible for the ultimate demise of the host.

In humans, the causes of prion diseases can be genetic (due to specific mutations in the host’s PrP gene), acquired (due to infections, such as exposures to kuru, BSE or other prion-contaminated materials), or sporadic (of unknown origin, but usually presumed to be due to spontaneous prion formation in the individual). The vast majority of human prion diseases are sporadic, the most common being sporadic Creutzfeldt-Jakob disease (sCJD), which has an incidence of about 1 case per million population per year world-wide. A number of different mutations in the PrP gene can cause a variety of familial human prion diseases, with some mutations being fully penetrant (always causing disease in people carrying the mutation), and others being less penetrant. The clinical symptoms and progression can vary markedly between prion disease types and individuals, but can include dementia, incoordination, insomnia, hallucinations, muscle stiffness, confusion, fatigue, and speaking difficulties.

There are also important prion diseases of animals. BSE arose as a major epidemic in cattle due to what might be described as “agricultural cannibalism” in the 1990’s. Consumption of BSE-contaminated beef then caused nearly 200 cases of variant CJD in humans. However, preventative measures have nearly eliminated BSE and the occurrence of new vCJD cases. Chronic wasting disease of cervids is sweeping through North America at an alarming rate, with cases also arising in South Korea and Norway. Scrapie is a persistent problem in sheep and goats in many parts of the world.

Diagnosis and Treatment of Prion Diseases

Considerable strides have been made recently toward being able to diagnose human prion disease accurately and relatively non-invasively in living patients based on new prion-specific testing of cerebrospinal fluid, nasal swabbings, blood, urine or skin. For example, RT-QuIC testing of cerebrospinal fluid and/or nasal brushings can be nearly 100% accurate in diagnosing sCJD. These tests have the advantage of measuring the causative agent of prion disease, but have not yet been fully vetted and recommended officially by organizations such as the WHO. Otherwise, diagnoses of sporadic prion disease in humans depend primarily on a confluence of clinical signs, brain scans, electroencephalograms, and other biomarker measurements, which collectively can have high diagnostic sensitivity, but are not fully specific for prion disease.

Notwithstanding the recent advances in the new prion tests described above, current guidelines indicate that definitive diagnosis of sporadic or acquired prion disease requires neuropathological examination of brain tissue obtained by biopsy (rare) or autopsy. I expect that the guidelines will soon be changed to include the new less-invasive intra vitam tests for prions. Unfortunately, although the above improvements in the early definitive diagnosis of prion disease should improve prospects for developing and implementing therapeutics, no treatments are currently available that have proven to be effective in the clinic.

Open Question and Future Directions

Key questions that remain in the mammalian prion disease field are: 1) What are the self-propagating structures of prions and how do they vary with prion strain? 2) How do prions damage the brain? 3) How can we prevent or repair the damage to treat these diseases? 4) What are the most relevant transmission mechanisms for prion diseases in humans and animals? 5) Which, if any, prion diseases of animals (besides BSE) have zoonotic potential to cause disease in humans? 6) To what extent can other pathogenic misfolded proteins with self-seeding activity behave like PrP-based prions in being able to propagate within or between individuals to cause disease?

These findings raise urgent questions about whether these many protein misfolding diseases, which are often much more common than the PrP-based prion diseases, might be transmissible in humans or animals under practical real-life circumstances. CJD has been transmitted between people via tissue transplants, cadaver-derived hormone injections, blood transfusions, and contaminated medical instruments. A contributing factor in such iatrogenic transmissions is the fact that prions are often not fully inactivated by standard clinical disinfection procedures. Whether other types of potentially prion-like disease-associated protein aggregates might be similarly resistant to inactivation and then capable of initiating or accelerating pathogenic processes in people remains to be determined. I know of no epidemiological indications that this is the case, but further scrutiny seems warranted.


What are human prion diseases?

Prion diseases are a group of neurodegenerative diseases caused by prions, which are “proteinaceous infectious particles.” For some background, first see this introduction to prions. Prion diseases are caused by misfolded forms of the prion protein, also known as PrP. These diseases affect a lot of different mammals in addition to humans – for instance, there is scrapie in sheep, mad cow disease in cows, and chronic wasting disease in deer.

The human forms of prion disease are most often the names Creutzfeldt-Jakob disease (CJD), fatal familial insomnia (FFI), Gertsmann-Straussler-Scheinker syndrome (GSS), kuru and variably protease-sensitive prionopathy (VPSPr). All of these diseases are caused by just slightly different versions of the same protein, so we refer to them all as prion diseases.

Even though prion diseases do come in slightly different forms, they have a whole lot in common. In each disease, the prion protein (PrP) folds up the wrong way, becoming a prion, and then causes other PrP molecules to do the same. Prions can then spread “silently” across a person’s brain for years without causing any symptoms. Eventually prions start to kill neurons, and once symptoms strike, the person has a very rapid cognitive decline. Most prion diseases are fatal within a few months, though some can last a few years [Pocchiari 2004].

Prion diseases in humans are fairly rare – about 1 to 2 people out of every 1 million people dies of a prion disease each year [Klug 2013]. Prion diseases can come about in one of three ways: acquired, genetic or sporadic.

Acquired means the person gets exposed to prions and becomes infected. Even though prions are scary, they’re very hard to catch, and so infection is the least common way of getting a prion disease. There was a famous epidemic of kuru, a prion disease which was passed from person to person by cannibalism, in Papua New Guinea, but this has now mostly subsided. Then there is mad cow disease or bovine spongiform encephalopathy. This disease passed from cows to humans through contaminated food. The human form of the disease is called variant Creutzfeldt-Jakob Disease (vCJD) and has killed about 200 people in the U.K. since 1994 [UK CJD Survelliance]. Today there are only a few people are dying of this disease each year. There have also been cases where prion disease has been transmitted via contaminated surgical instruments, human growth hormone supplements, or transplants of dura mater (a tissue surrounding the brain). These medical infections are called “iatrogenic” infections.

Prion diseases can also be genetic. First, let’s recall some biology basics. DNA contains instructions which get re-written in RNA, and then the instructions in RNA get translated into protein. So changes in a person’s DNA can cause changes in the proteins their cells produce. Everyone has a gene called PRNP which codes for the protein called PrP, and most of the time this protein is perfectly healthy and fine. Some people have mutations in the DNA of their PRNP gene, which cause it to produce mutant forms of PrP. These mutant forms don’t form prions instantly, and most people with PRNP mutations live perfectly healthy for decades. But as people get older, the mutant forms of PrP are more and more likely to fold up the wrong way and form prions. Once they do, the person has a rapid neurodegenerative disease.

Some people refer to genetic prion diseases as “inherited” or “familial” prion diseases. We prefer not to use these terms: just because a disease is genetic doesn’t mean it’s inherited or familial. Every DNA mutation has to start somewhere, so some people with genetic prion disease are the first in their family – they didn’t inherit the mutation, and it’s not familial. According to one estimate, 60% of genetic prion disease patients have no family history of the disease [Bechtel & Geschwind 2013].

Finally, prion diseases can simply be sporadic, meaning we don’t know why they happen. Some people think that sporadic prion diseases happen when one prion protein just misfolds by chance, and then spreads from there. Others think that the disease may start with one cell that has a spontaneous DNA mutation and starts producing mutant PrP. We don’t know what the real answer is. Either way, the effect is that people with no previous exposure to prions and no mutations in (most of) their DNA end up getting a prion disease out of nowhere.

The sporadic form of prion disease is by far the most common. It’s often estimated that human prion disease cases are 85% sporadic, 15% genetic and < 1% acquired [Appleby & Lyketsos 2011, CDC Fact Sheet, UCSF Primer].

So prion diseases can be categorized by where they came from: acquired, sporadic, and genetic. But as mentioned at the top of this post, you’ll also hear prion diseases categorized a different way, most often as Creutzfeldt-Jakob disease (CJD), fatal familial insomnia (FFI), and Gerstmann-Straussler-Scheinker (GSS) syndrome. The origin and use of these names can be confusing. The names were originally used to categorize patients by their symptoms, but later came to refer to particular strains or genetic varieties of prion disease.

For instance, the name fatal familial insomnia was originally applied to a family with a genetic disease with insomnia as the first and foremost symptom [Lugaresi 1986]. After it was later found that a particular genetic mutation caused this disease [Medori 1992], people started using FFI to refer to the disease caused by that one particular mutation, even though for some patients insomnia isn’t a major part of the disease [Zarranz 2005]. Later on scientists discovered a non-genetic form of FFI and called it sporadic fatal insomnia (sFI) [Parchi 1999], but other people see it as a subtype of CJD and refer to it as “MM2 thalamic Creutzfeldt-Jakob disease” [Moda 2012].

To add another layer of complexity, new types of prion disease are still being discovered that don’t fit into any of the original three categories (CJD, FFI or GSS). For example, the most recent new form was dubbed “variably protease-sensitive prionopathy” (VPSPr) [Zou 2010]. That’s quite a mouthful.

Since the naming system can be confusing, we usually avoid it altogether and simply refer to all of these diseases as prion diseases. For genetic prion diseases, it is useful to name the exact mutation – for instance, E200K or P102L (for how to interpret these numbers and letters see our upcoming primer on genetic prion diseases). As for sporadic prion diseases, scientists have a system of biochemical subtypes such as “MV1″, “VV2″, “MM2 cortical” and so on.

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. The diagram below illustrates how just one protein – PrP (green) – can fold up in several different ways, creating several different strains of prion (red).

There are actually a dizzying number of different forms of human prion disease. Kuru and vCJD, two strains that people have acquired by infection, are probably the most famous but also the most rare. There are also at least 6 strains of sporadic prion disease [Parchi 2011] and over 40 genetic mutations that cause prion disease [Beck 2010].

Many of these different prion strains act pretty differently. They come from different sources, cause different disease symptoms and strike people of different ages. But since they’re all caused by the same protein – PrP – we’re hopeful that it will be possible to find one treatment that will treat all of these different diseases.