Difference between prions and amyloid proteins?

Difference between prions and amyloid proteins?

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Amyloid and prions are misfolded proteins, but what, if any, is the difference between them?

Is amyloid a type of prion with a fibrillar structure?

Amyloids are protease resistant insoluble fibrils formed because of (mis)folding and aggregation of soluble proteins (Rambaran and Serpell, 2008, Sabate et al., 2015). The first definition of prion was given by Prusiner (1982):

Because the novel properties of the scrapie agent distinguish it from viruses, plasmids, and viroids, a new term "prion" is proposed to denote a small proteinaceous infectious particle which is resistant to inactivation by most procedures that modify nucleic acids.

Many prionic diseases are characterized by amyloid fibril formation and therefore some (if not many) researchers consider prions to be a subset of amyloids.

Prions are considered a subclass of amyloids in which protein aggregation becomes self-perpetuating and infectious.
(Sabate et al., 2015)

However, the amyloid structure formation is not essential either for the autopropagation or disease progression (Moore et al., 2014).

When wild-type C57BL/10 mice are infected intracranially with the RML mouse prion strain, PrPSc accumulates in diffuse nonamyloid deposits and brain pathology is distinguished by the hallmark gray matter spongiosis for which TSEs are named. Conversely, when transgenic mice homozygous for PrPC lacking the GPI anchor (Tg44 or “anchorless” mice) are infected with the same RML strain, the incubation time is longer and PrPSc accumulates in dense perivascular amyloid plaques with little or no gray matter spongiosis.9−11 Similar amyloid PrPSc deposition and disease resulting in death has been observed in humans with an aberrant stop codon in the C-terminal portion of the PrP sequence, resulting in the generation of PrP lacking the GPI anchoring group as well as some amino acid residues.13−16 Thus, GPI-anchoring of PrPC to the plasma membrane appears to be a primary factor determining the type of PrPSc deposition and the development of brain pathology.

You can say that the prion protein PrPC is amyloidogenic but it is not an amyloid.

There are non-pathogenic (and in fact useful prions) found in fungi. Many of these beneficial prions also form the amyloid (like) structure but they can be disaggregated by chaperones (Wickner et al., 2018). Now again, it is not essential for these beneficial prions to form an amyloid structure.

Prions (defined as “infectious proteins”) need not be amyloids. The vacuolar protease B (Prb1p) of Saccharomyces cerevisiae is made as an inactive precursor that is normally cleaved and so activated by the action of protease A (Pep4p) [32]. However, in the absence of Pep4p, mature active Prb1p can activate its own precursor [33]. This self-activation can propagate and pass from cell to cell in an infectious manner, acting like a prion, and named [BETA] [34]. In the absence of Pep4p, [BETA] is necessary for meiosis and spore formation and for survival in stationary phase [34]. It is thus a functional prion.

[SMAUG+] is another example of a non-amyloid yeast prion which has beneficial effects (Chakravarthy et al., 2019 and Itakura et al., 2019; Jarosz group). Unlike Prb1p, [SMAUG+] actually forms self-propagating aggregates.

My summary

Many known prions are amyloidogenic and can switch to amyloid form. However, as per the definition, prions are "infectious" or in other words, self-propagating proteins. What qualifies as a prion depends on our definition. Mode of action of most known prions is catalyzing a change in the protein fold. Wickner et al (as quoted above) reason that the original definition does not explicitly include the mode of action and hence proteins that activate themselves via proteolysis should also be considered prions. Jarosz's group has shown an example of a non-amyloid prion that forms self-propagating aggregates. It quite likely that more such proteins will be discovered in near future.

In any case, "amyloid" is a structural property whereas "prion" is a functional property and they cannot be considered a sub/superset of one another, even if they happen to be correlated.

The bottomline is:
Amyloid is a form of supramolecular protein structure which is often formed by many prionic proteins. However, not all amyloid forming proteins are prionic and not all prions necessarily form amyloids.

The protean prion protein

The prion protein, PrP, can adopt at least 2 conformations, the overwhelmingly prevalent cellular conformation (PrP C ) and the scrapie conformation (PrP Sc ). PrP C features a globular C-terminal domain containing 3 α-helices and a short β-sheet and a long flexible N-terminal tail whose exact conformation in vivo is not yet known and a metastable subdomain with β-strand propensity has been identified within it. The PrP Sc conformation is very rare and has the characteristics of an amyloid. Furthermore, PrP Sc is a prion, i.e., it is infectious. This involves 2 steps: (1) PrP Sc can template PrP C and coerce it to adopt the PrP Sc conformation and (2) PrP Sc can be transmitted between individuals, by oral, parenteral, and other routes and thus propagate as an infectious agent. However, this is a simplification: On the one hand, PrP Sc is not a single conformation, but rather, a set of alternative similar but distinct conformations. Furthermore, other amyloid conformations of PrP exist with different biochemical and propagative properties. In this issue of PLOS Biology, Asante and colleagues describe the first murine model of familial human prion disease and demonstrate the emergence and propagation of 2 PrP amyloid conformers. Of these, one causes neurodegeneration, whereas the other does not. With its many conformers, PrP is a truly protean protein.

Citation: Requena JR (2020) The protean prion protein. PLoS Biol 18(6): e3000754.

Published: June 25, 2020

Copyright: © 2020 Jesús R. Requena. 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 funded by the Spanish Ministry of Industry and Competitiveness (grant BFU2017-86692-P), partially supported with EU FEDER funds. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The author has declared that no competing interests exist.

Provenance: Commissioned externally peer-reviewed.

Prions were defined by Stanley Prusiner in 1982 as “proteinaceous infectious particles” [1]. This was likely a euphemism for “infectious protein,” a definition that would have been too explicit at the time. The first prion to be discovered was PrP Sc , identified as the causative agent of scrapie, a transmissible neurodegenerative disease of sheep [2]. Later, its normally folded precursor, PrP C , was found. Therefore, although PrP means “prion protein,” PrP C is not a prion, rather, it can be refolded into a prion. Indeed, PrP Sc prions propagate by templating their peculiar conformation into PrP C . This occurs through a process in which formation of hydrogen bonds between amino and carbonyl groups of the templating and templated polypeptides is likely to play a key role [3,4] (Fig 1). Prions are infectious because they can transmit from one individual to another, typically but not always (vide infra) by an oral route (Fig 1).

(1) Formation of hydrogen bonds between amino and carbonyl groups of the templating and templated polypeptides has been proposed as the key mechanism in prion propagation [3,4]. Carbonyl and amino groups in the edge β-strands of PrP Sc are ready to form hydrogen bonds with an incoming, partially unfolded PrP polypeptide, coercing its refolding to form fresh β-strands. This way PrP Sc can propagate throughout the brain. (2) Its infectious nature comes from the fact that PrP Sc , introduced in a different brain through oral, parenteral, or other means, can propagate there. PrP, prion protein PrP Sc , prion protein with scrapie conformation.

Although at first sight it might appear so, prions do not contradict Anfinsen’s principle. The prion protein, encoded by the Prnp (human: PRNP) gene, time and again folds into a perfectly defined conformation, PrP C , featuring a globular C-terminal domain containing 3 α-helices, a short β-sheet (residues approximately 125–231), and a long flexible N-terminal tail (residues 23–124) [2]. The exact conformation of the tail in vivo is not yet known. A metastable subdomain with β-strand propensity has been identified within the 113–120 region [5]. It is only under rare circumstances that PrP C refolds to adopt the alternative prion conformation, PrP Sc (Fig 2). PrP Sc is often an amyloid, and therefore, its conformation must allow stacking to form this kind of fibrillary structure [3]. Actually, adopting an alternative amyloid conformation is something that all proteins can do under certain circumstances, as demonstrated by Dobson and collaborators [6]. Any protein, no matter how well behaved and stable, if submitted to certain experimental conditions, such as low pH and/or presence of denaturants, will adopt an amyloid conformation [6]. In fact, the amyloid conformation is the most stable one, and all other native folds are believed to be kinetically trapped intermediate states [6]. Furthermore, all amyloids catalyze transition of their normal fold into the amyloid fold, a phenomenon known as “seeding” [7]. In summary, prions are just a special type of amyloids, and all proteins can be amyloids, so prions are not that strange.

The Prpn/PRPN gene is transcribed and translated into the PrP polypeptide, which readily adopts the PrP C conformation (1). PrP C can refold to adopt one of several PrP Sc strain conformations (2). These can be pathogenic (skull and bones sign) or not (face sign). PrP Sc is depicted as stacked cylinders assuming that it is a 4Rβ [4], although its nature is not settled without doubt yet [25]. Different PrP Sc strains exhibit different degrees of resistance to PK. PK-sensitive PrP Sc exists (transparent cylinders). PrP C can be also refolded in vitro and adopt a PIRIBS amyloid conformation that can propagate in the brain upon inoculation and can be further transmitted by inoculation as an infectious agent (3). The darker shade indicates a PK-resistant C-terminus. During successive passages, deformed templating results in evolution of this conformer to PrP Sc (4). Different mutations in PRNP result in PrP C (5) with a higher tendency to refold into a variety of propagative PrP conformers that form insoluble aggregates. In tg 117V mice, they include PK-sensitive, pathogenic PrP Sc (6) and a transmissible, nonpathogenic PrP amyloid (7) with a characteristic pattern of resistance to PK (an approximately 8-kDa band corresponding to a segment that is different to that seen in the propagative amyloid described above and is signaled by the darker shading). It should be noted, however, that a recent study suggests that the approximately 8-kDa fragments are infectious and pathogenic and that they might exhibit a 2-rung solenoidal architecture [17]. A 145Stop mutation in PRNP results in PrP23-144 that folds into a propagative and pathogenic PIRIBS amyloid (8). During passage to wild-type mice, deformed templating occurs, resulting in emergence of PrP Sc . PK, proteinase K PIRIBS, parallel in register beta strand PrP, prion protein PrP C , prion protein with cellular conformation PrP Sc prion protein with scrapie conformation.

Prions do not contradict the Central Dogma of molecular biology either. In order to propagate, the prionic conformation PrP Sc needs to recruit fresh PrP C units and coerce them to refolding. Such PrP C units are encoded by DNA transcribed to RNA and translated in ribosomes (Fig 2). Knock off the Prnp gene and there is no transmission of prions [2]. Again, prions are not that unusual, biologically speaking, contrary to their aura as obscure, bizarre proteins, acquired 25 years ago during the bovine spongiform encephalopathy (BSE) epizootic.

As I write this Primer at home, on day 30 of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic confinement, like millions around the world, it is inevitable to remember how about 20 years ago, everyone was anxiously looking at the curve of new cases of variant Creutzfeldt-Jakob disease (vCJD), the fatal neurodegenerative disease caused by bovine prions transmitted to humans [8]. At the time, it was not known whether bovine prions were very transmissible to humans or not. Virtually all Britons (with the exception of a few vegans) and countless other Europeans had been exposed to bovine prions, and considering that prion diseases are invariably fatal, fears of a disaster of apocalyptic proportions gripped epidemiologists and the general public [8]. Fortunately, bovine prions eventually proved to be very poorly transmissible to humans, and only approximately 200 deaths occurred, sad as all deaths are. Why is the transmission barrier between bovine prions and humans so high? We do not know. The sequences of bovine and human PrPs contain some amino acid differences, but how exactly these differences impinge in the templating process (Fig 1) to create a transmission barrier between bovine PrP Sc of human PrP C is not yet clearly understood.

Prion transmission barriers arising from differences in PrP sequence are not the only ones that exist. The classic studies performed by Bessen and Marsh showed the existence of 2 different kinds of prions in Syrian hamsters, both with the same sequence, that transmit differently. Thus, the Hyper PrP Sc “strain” can be transmitted between hamsters by both intracerebral and intraperitoneal inoculation, whereas the Drowsy strain can be transmitted by intracerebral inoculation only [9]. Furthermore, these 2 strains exhibit distinct biochemical and biological properties. In fact, their names refer to phenotypic characteristics of hyperactivity or lethargy exhibited by infected animals. In an elegant study, Safar and colleagues showed that PrP Sc strains must be subisoforms of PrP Sc , variations on a general structural theme [10]. This meant that there were not just 2 PrP conformers, PrP C and PrP Sc : Rather, there were PrP C and several relatively similar but distinct PrP Sc conformers.

Once the BSE epizootic faded away (fears of a second wave of vCJD affecting more resistant individuals with longer incubation times have not materialized), attention was turned to sporadic prions. PrP C sometimes refolds to PrP Sc spontaneously, in the absence of any preexisting PrP Sc template. It is a very rare event, with a yearly incidence of 1–2 cases/million people [2,8] and likely similar rates in other mammalian species. Once a small pool is formed, PrP Sc prions propagate throughout the brain by templating. Sporadic human prions are, however, unable to infect another brain, unless they are taken there through specific and relatively uncommon events. These include ritual cannibalism (as in the case of kuru [2,8]), industrial cannibalism (as in the case of BSE [2,8]), and iatrogenesis (as in several instances of transmission through surgical instruments or treatment with brain-derived, prion-contaminated growth hormone [2,8]). In contrast, ovine scrapie and cervid chronic wasting disease (CWD) PrP Sc prions are shed in feces and urine and are therefore readily transmitted between sheep and cervids. In fact, CWD and scrapie have become endemic in certain geographical regions [11]. But this only reflects differences in their physiology, not intrinsic differences in structure. In fact, sporadic human prions and “infectious” CWD and scrapie prions can be experimentally transmitted by inoculation with similar ease into appropriate transgenic (tg) mouse models [2,8].

Until recently, this was not the case, however, for familial prions. A number of mutations in the PRNP gene result in fatal neurodegenerative diseases whose phenotypes overlap with those of sporadic prion diseases [8]. In all familial cases, deposits of a PrP amyloid are found postmortem in the brain. It has therefore been assumed that these mutations predispose to conformational change in the expressed PrP protein, leading to the generation of disease-related PrP assemblies that propagate by seeded protein misfolding. Such propagative PrP assemblies, with amyloid characteristics, were therefore believed to be prions. Yet infectious transmission (i.e., transmission between brains) of familial pathogenic prions was not unequivocally achieved for a long time [8]. This might seem an oddity, of interest to punctilious specialists only. But it is not. First, if aggregates of mutant PrP were not infectious, were they prions? Could one be sure that at least, they propagated throughout the affected brain by seeded misfolding, or did they just misfold and clump in situ? And, if they were not infectious, was it because they display an additional conformation that is neither PrP C nor any of the PrP Sc subtypes?

But the picture was even more complicated. Mutant PrP aggregates could actually be transmitted by intracerebral inoculation. They were shown to propagate in the brain of recipient animals, which accumulated PrP amyloid deposits. Serial passage was also demonstrated. Yet these animals did not show signs of neurodegenerative disease [12,13]. This suggested that bona fide (i.e., infectious) prions could be innocuous. But then, what causes the brain damage seen in familial prion diseases? Yet another PrP conformer? Some unidentified pool of PrP Sc ?

Asante and colleagues finally succeeded in experimentally transmitting a human familial disease. They showed that the aggregates of PrP with the A117V mutation, found in the brain of individuals suffering the deadly neurodegenerative Gerstmann-Sträussler-Scheinker (GSS) disease, could be transmitted to tg mice expressing human PrP on a mouse PrP null background, and along them, the disease [14]. This considerably simplified things. However, in order to minimize the transmission barrier associated to the A117V mutation, and therefore facilitate transmission, the recipient tg mice were engineered to carry the A117V mutation. Strikingly, these mice did not spontaneously develop a familial prion disease. This was very convenient: Had they developed the disease, it would have been impossible to assess the transmissibility of the HuPrP(A117V) aggregates present in the inoculum. But why did they not get spontaneously ill? Were they not producing prions in their brains?

In this issue of PLOS Biology, Asante and colleagues definitively close the circle by showing that some of the tg mice expressing human PrP 117V do spontaneously generate bona fide pathogenic prions [15]. Inoculation of abnormal PrP 117V assemblies found in their brains into other 117V tg mice produced, in some cases, a fatal neurodegenerative disease. The fact that the noninoculated mice do not develop the disease is therefore just a matter of timing: The longevity of mice is short, and the pathogenic prions accumulating in their brains do not have time to cause disease in all cases. The tg HuPrP117V mice can be considered a definitive mouse model of human familial prion disease.

Although the 2 studies by Asante and colleagues simplify our understanding of prion propagation, by allowing generalizations, they also bring fresh questions. The aggregates of mutant PrP 117V seen in affected brains show a very peculiar pattern of resistance to proteinase K (PK). PK has been used for many years as an important tool to characterize prions. Typically, PrP Sc is partially resistant to PK, which trims its supposedly flexible N-terminal tail, generating a characteristic triplet of variably glycosylated resistant fragments termed PrP27-30. Small amounts of such triplet were seen in the infectious brain samples from PrP 117V tg mice, but only under certain circumstances, indicating that PrP Sc exists in these brains but that it exhibits an unusually low resistance to PK [15] (Fig 2). The existence of PK-sensitive PrP Sc has been known for a long time. Currently, it is not completely clear whether sensitivity to PK is a feature that depends on the tertiary or quaternary structure of a particular PrP Sc strain.

Strikingly, these samples also contain noncanonical PK-resistant approximate 8-kDa fragments resulting from a double N- and C-terminal truncation. Similar fragments are detected in the brains of many prion diseases termed “atypical” [16]. The most parsimonious explanation for these fragments would be that they derive from a single PrP Sc conformer. However, the interpretation of Asante and colleagues is that in their particular model, they come from 2 different PrP 117V conformers [14,15]. Among other considerations, the lack of correlation between accumulation of amyloid plaques in the brain and appearance of disease militates in favor of such interpretation. Thus, the doubly truncated fragment is proposed to derive from a transmissible but not infectious PrP amyloid conformer (Fig 2). It should be noted, however, that in a study published almost simultaneously to the one by Asante and colleagues, Vanni and colleagues inoculated GSS A117V brain homogenate to Bank voles (Myodes glareolus, a rodent that is very susceptible to prion infection), provoking a transmissible prion disease in them [17]. The brains of these animals also contained aggregates that upon treatment with PK yielded a doubly N- and C- truncated fragment. Then, Vanni and colleagues partially isolated the PK-resistant material and showed it to contain all the infectivity harbored in these brains [17]. These results strongly suggest that the infectivity in their model is associated with the PrP conformer that yields the approximately 8-kDa doubly truncated PK-resistant band. Although there seems to be a contradiction between the interpretations provided by these 2 groups, it should be noted that the models are different. It is particularly noteworthy that the infected Bank voles do not accumulate large amyloid deposits as the tgHuPrP117V do. In fact, electron microscopy images of the semipurified PK-treated infectious PrP material showed it not to be fibrillary, consisting of amorphous aggregates [17]. Further studies will be required to harmonize these fascinating results.

A propagative but noninfectious PrP amyloid isoform has been described by Baskakov and colleagues [18]. However, such amyloid yields C-terminal PK-resistant fragments, so it is not structurally identical to the one propagating among 117V tg mice. Furthermore, in successive passages, besides this PrP amyloid, bona fide PrP Sc was seen to emerge with its characteristic PK-resistant triplet, and eventually, clinical disease appeared (Fig 2). This is the opposite of the results described by Asante and colleagues in which PK-sensitive PrP Sc co-propagating along nonpathogenic PrP amyloid eventually faded away [15]. Baskakov and colleagues coined the term “deformed templating” to refer to the phenomenon by which their propagative amyloid slowly gives rise to PrP Sc [18].

So the catalogue of PrP conformers has considerably expanded by now (Fig 2): There is PrP C different versions (strains) of PrP Sc , some of which are resistant, whereas others are extremely sensitive to PK and at least 2 distinct propagative PrP amyloids that can be serially transmitted between animals by inoculation, are not pathogenic, and generate distinctive patterns of PK-resistant fragments. Are these transmissible PrP amyloids prions? According to the original definition [1], yes, but they are hardly contagious at all: One must inoculate them intracerebrally to propagate them from brain to brain.

The structure of PrP C is very well known [2]. But what about the other confomers? All of them are amyloids, but they exhibit very different biochemical and biological properties. The distinctive structural characteristic of amyloids is that the β-strands are stacked perpendicularly to the long axis of the amyloid. These β-strands are held together by an array of hydrogen bonds aligned with such axis. Currently, there are only 2 structural amyloid models relevant to propagative PrP: the parallel in register beta strand (PIRIBS) structure and the 4-rung β-solenoid (4RβS). In the PIRIBS structure, each PrP molecule is a flat, serpent-like structure. Different PrP molecules stack on top of each other “in register,” this is, each amino acid residue is exactly on top of the equivalent residue in the preceding PrP monomer [19]. Solid-state NMR and electron paramagnetic resonance (EPR) spectroscopy data strongly suggest that the nonpathogenic, propagative amyloid described by Baskakov and collaborators features a PIRIBS architecture [20]. Smaller PrP fragments are also known to fold into PIRIBS structures [21]. Another propagative (but this time pathogenic) PIRIBS amyloid comprising PrP23-144 subunits has been described by Surewicz and colleagues [22]. It should be considered a bona fide PIRIBS PrP prion, but because it comprises a truncated version of PrP, it must be excluded from the catalogue of full-length PrP conformers. However, it is mentioned here for 2 reasons: On the one hand, an amber mutation of PrP (PrP145Stop) exists that results in expression of truncated PrP23-144 and leads to a familial prion disease. On the other, the characteristic N- and C-truncated fragment, resulting from PK treatment of A117 propagative, nonpathogenic PrP amyloid, involves a similar C-truncation, so it is tempting to speculate that both amyloids share a similar architecture (Fig 2). It should be noted that during successive passage of PrP23-144 prions in wild-type mice, classic PrP Sc also emerges, as in the cases described by Baskakov and colleagues. [18]. It is not clear to what degree each conformer of PrP contributes to pathogenesis. At this point, it is worth mentioning that some authors have suggested that even in simpler cases of prion disease such as sporadic ones, PrP Sc is not the pathogenic conformer: Rather, a “toxic” species exists that derives from PrP Sc [23]. Yet another possible conformer, whose discussion lies outside of the scope of this primer.

Mammalian Prion Strains Dictate Differential Pathological Consequences

Like other fatal human neurodegenerative diseases, transmissible spongiform encephalopathies (TSEs), or prion diseases, have cases that arise sporadically (Creutzfeldt-Jakob disease [CJD]) or are inherited (fatal familial insomnia and Gerstmann-Sträussler-Scheinker syndrome) [1]. Remarkably, prion diseases can also be acquired by infection (e.g., kuru in humans). TSEs afflict a wide variety of mammalian species (e.g., scrapie in sheep, chronic wasting disease in cervids, and bovine spongiform encephalopathy [BSE] in cattle). These disorders are caused by conversion of the normal, host-encoded protein, PrP C , to an abnormal infectious conformation called PrP Sc that generally adopts an amyloid-like structure. The widely accepted prion hypothesis suggests that PrP Sc is the sole transmissible agent of prion diseases, thus making it distinct from conventional pathogens having a nucleic acid component. However, it was long unclear how a protein-based infectious agent could explain the existence of prion strains.

Even early observations of prion diseases describe considerable diversity in disease symptoms with different PrP Sc isolates [2]. This typically presents as variation in incubation period (the time from infection to the onset of symptoms) or the distribution patterns of PrP Sc or spongiform pathology in the brain. In addition, certain prion isolates show different degrees of transmissibility between species, a phenomenon called the “species barrier,” whereby transmission between different species is generally less efficient than transmission within the same species. This was brought to the public's attention in the mid-1990s with the outbreak of BSE (commonly referred to as “mad cow disease”) and subsequent transmission to humans, causing a novel disease called variant CJD [2]. Some argued that the variation in pathology and transmissibility related to prion strains indicated that the infectious agent must have a nucleic acid component or be encoded by changes in the PrP sequence in an analogous fashion as genetic polymorphisms that distinguish different strains of viral or bacterial infections. However, distinct prion strains were isolated that had an identical primary structure, suggesting that the physical basis of prion strains was not simply determined by sequence variation. Indeed, these early studies demonstrated that two different strains of transmissible mink encephalopathy showed different resistance to proteases, suggesting that prion strains represent distinct aggregate conformations of the same protein [3].

Evidence for human-to-human transmission of Aβ aggregates

Between 1958 and 1985, several thousand people mostly in the United Kingdom, France, and the United States were treated for short stature with injections of human growth hormone extracted from the brains of cadavers. This treatment was discontinued in 1985 after some patients were found to have acquired the human prion disease, Creutzfeldt-Jakob disease, from injected material contaminated with infectious PrP aggregates [6]. The cadavers from where the contaminated growth hormone had been extracted must have had undetected PrP aggregates within their brains. In a recent study published in the journal Nature, researchers from University College London performed autopsies on 8 individuals, all between the ages of 36 and 51, who had died from this acquired prion disease [6,7,8]. The researchers found PrP aggregates in the brains of all 8 patients, as expected however, they were surprised to also find extensive Aβ clumps within the brains of 4 of the patients, and mild Aβ clumping in 3 more patients. Although none of these patients had been diagnosed with Alzheimer’s disease, it is extremely rare to find this type of Aβ aggregation in this age group, especially considering that the researchers found that none of these patients had any genetic mutations known to increase the likelihood of early onset Alzheimer’s. This finding caused the researchers to wonder: Could these Aβ aggregates also have been transmitted from the brains of the cadavers?

To confidently answer that question, the researchers needed to test a couple of hypotheses. First, does having PrP clumps make it more likely that a person’s brain will also show Aβ aggregation? To rule out this possibility, the researchers looked for Aβ aggregation in 116 other patients who had died from sporadic or inherited (i.e. not infectious) prion diseases. These 116 patients had not acquired their prion disease from infected human growth hormone. They found that none of the patients in this control group had similar Aβ aggregation. They next asked whether Aβ aggregates could be found in the region of the brain where human growth hormone had been extracted from the cadavers. They examined the brains of an additional 49 patients who had died from Alzheimer’s, and indeed found Aβ aggregates in this particular brain region in 7 of these patients.

Based on their comprehensive findings (summarized in Figure 3), the researchers concluded that the extensive Aβ aggregates in these patients were likely triggered by small Aβ clumps contained in the cadaver-extracted human growth hormone. These cadaver Aβ clumps had very likely led to the misfolding and aggregation of normal Aβ protein in these patients’ brains. This finding represents the first observation of human-to-human Aβ transmission and perhaps the first indication that Alzheimer’s disease may be transmitted among humans in a similar fashion as prions.

Figure 3: Summary of new findings. Autopsies of 8 patients who died from human growth hormone-acquired prion disease revealed that Aβ aggregates may be transmitted from human to human.

Prions, Nearly Indestructible and Universally Lethal, Seed the Eyes of Victims

It was probably only a matter of time until someone connected the dots.

Prions &ndash infectious proteins -- had turned up in the eyes of victims of prion diseases.

Infected donor corneas had transmitted prion disease to recipients on at least a few occasions.

And often, patients who later turn out to be infected with prions have eye trouble for which they seek medical attention and testing before they are aware they are infected.

The possibility was horrifying. But it demanded investigation.

Prions are proteins, and, as every biology student knows, proteins are dependent on DNA and RNA for their existence. Yet prions have stumbled upon a way to be self-replicating nonetheless. Their diseased shape induces proteins of similar sequence but healthy shape &ndash found abundantly in all nervous tissue -- to misfold when they collide with a prion. Now they are infectious too, part of a relentless and lethal domino effect.

The diseases they cause are grim. Mad Cow Disease is the most famous, but kuru also possesses a certain notoriety thanks to its unorthodox mode of transmission. Although uncommon, prion diseases are incurable and bring dementia swiftly followed by death. In the case of spontaneous Creutzfeldt-Jakob Disease (sCJD), the most common prion disease, half of patients are dead within six months of symptom onset. That figure reaches 95% within a year. In a particularly vexing twist, prions are also nearly impervious to destruction, even when attacked using a strenuous combination of disinfectants, heat, and pressure.

As you can imagine, this makes prions difficult to eliminate from infected tissues and equipment. In addition to corneal transplants, sCJD has also been transmitted by transplants of brain tissue called dura mater, growth hormone from cadavers, and perhaps most worryingly, neurosurgical instruments. So any method that might throw prions into the path of uninfected people deserves scrutiny.

Enter the study published in November in the journal mBio by a team of American scientists that found the eyes of human prion victims are loaded with infectious particles even before they have begun to exhibit symptoms. Further, these particles are present on the surface of their corneas, the covering of the eye. 100% of the eyes of 11 sCJD victims who donated their bodies for study were seeded throughout with prions. 100% of their corneas contained prion seeding of a &ldquolow to moderate&rdquo degree. Because the cornea is enervated, the prions, which prey on proteins found in neurons, may be reaching the surface via these tiny neural conduits.

The retina &ndash the light sensing layer at the back of the eye -- was most densely packed with prions in the inner and outer plexiform layers. They were easily visible in tissue stains.

Normal retina (left) and diseased retina (right). Prions visible as a brownish stain in the inner and outer plexiform layers. Credit: Orrù et al. 2018

In half of the 11 cases, the concentration of prions in the retina approached levels found in the brain, the epicenter of prion activity.

On the plus side, this finding, combined with the relative ease of assessing the retina, suggests a new target for traditionally tricky CJD diagnosis by non-invasive methods as electroretinograms.

On the other hand, all remaining implications are disturbing. It&rsquos unknown how early in the disease process prions appear in the eyes of humans, but in rodents, they are present prior to the onset of disease. About 40% of sCJD patients develop eye-related symptoms serious enough to warrant a consultation with an ophthalmologist. Somwhere between a quarter and a half go blind.

Undiagnosed CJD patients may seek testing. And the diagnostic equipment used to test them may then become contaminated, the authors write. They recommend single-use instruments or the adoption of new decontamination procedures for opthalmological equipment with better effectiveness on prions.

Meanwhile, corneal transplants are becoming increasingly popular worldwide. According to the authors, 185,576 were performed in 116 countries in 2012, a new high. The United States leads the world per capita, with 64,000 performed each year. The authors further recommend speeding and perfecting the development of synthetic corneas to reduce the need for donor corneas.

But there are yet more worrying implications of these findings.

As I wrote about at this blog earlier this year, there is a growing uneasiness that the clumping proteins associated with some of the most common and deadly neurodegenerative diseases behave in ways that are uncomfortably similar to prions.

One question suggested by this research is whether the eyes of Alzheimer&rsquos and Parkinson&rsquos patients are likewise filled with amyloid-beta, alpha-synuclein, and tau, and if that is the case, if the accumulation of those proteins in eyes might be exploited to aid diagnosis, a notoriously tricky proposition for these diseases.

Another is &ndash and I am entering deep speculative territory here, as in, no one actually qualified to render an opinion on this has said it, I&rsquom just putting two and two together in my head -- whether ophthalmological equipment could act as a vector for those diseases, as surgical equipment has already been hypothesized to do.

Don&rsquot skip your eye exam. But given the seriousness of the stakes, I hope that someone out there is investigating these hypotheses. Yes, the odds are low. But the stakes are very, very high.

Orrù, Christina D., Katrin Soldau, Christian Cordano, Jorge Llibre-Guerra, Ari J. Green, Henry Sanchez, Bradley R. Groveman et al. "Prion Seeds Distribute throughout the Eyes of Sporadic Creutzfeldt-Jakob Disease Patients." mBio 9, no. 6 (2018): e02095-18.

The views expressed are those of the author(s) and are not necessarily those of Scientific American.


Jennifer Frazer, an AAAS Science Journalism Award–winning science writer, authored The Artful Amoeba blog for Scientific American. She has degrees in biology, plant pathology and science writing.

Role of cellular prion protein in interneuronal amyloid transmission

Several studies have indicated that certain misfolded amyloids composed of tau, β-amyloid or α-synuclein can be transferred from cell to cell, suggesting the contribution of mechanisms reminiscent of those by which infective prions spread through the brain. This process of a 'prion-like' spreading between cells is also relevant as a novel putative therapeutic target that could block the spreading of proteinaceous aggregates throughout the brain which may underlie the progressive nature of neurodegenerative diseases. The relevance of β-amyloid oligomers and cellular prion protein (PrP C ) binding has been a focus of interest in Alzheimer's disease (AD). At the molecular level, β-amyloid/PrP C interaction takes place in two differently charged clusters of PrP C . In addition to β-amyloid, participation of PrP C in α-synuclein binding and brain spreading also appears to be relevant in α-synucleopathies. This review summarizes current knowledge about PrP C as a putative receptor for amyloid proteins and the physiological consequences of these interactions.

Keywords: Amyloid Cellular prion protein Neurodegeneration Proteinaceous species Spreading ‘Prion-like’ spreading.

Figure 4

Figure 4. Cosedimentation of PrP and its fragments with Aβ1–42 fibrils. (A) Schematic diagram of PrP fragments used. Full-length PrP or its fragments (2 μM) were preincubated in the absence (B) or presence of Aβ1–42 fibrils (20 μM) (C). Samples were then centrifuged, and pellets and supernatants were analyzed by SDS-PAGE. Symbols P and S refer to pellet and supernatant, respectively. (D) Percent fraction of PrP cosedimented with fibrils was determined by densitometric analysis of the gels.

PrP Induces Lateral Association of Preformed Aβ Fibrils

What is the structural basis of variant phenomena?

The structure of infectious PrP is not yet known, but infectious amyloids of the prion domains of Ure2p, Sup35p and Rnq1p each have an in-register parallel β-sheet structure (see, for example, [10]). Thus, each residue of the last monomer to join the filament contacts the same residue of the preceding monomer (Figure 1c). The register is maintained by hydrogen bonds between Gln or Asn (the so-called β-zipper) and possibly between Ser and Thr residues. A line of hydrophobic residues down the fiber will likewise have positive interactions, helping to keep the β-sheet in register. The location of turns, the contacts between β-sheets and the extent of β-sheet are thus transmitted to the newly joined monomer. Combined with chain breakage to make new seeds, this templating action can explain the heritability of prion strains/variants [11]. A weakly homologous or non-homologous (but still Q/N rich) monomer might interact with part of the monomer on the end of the filament, so that only part of its conformation was fixed. The remainder may form by some stochastic interaction with another monomer identical to itself (shown schematically in Figure 1c). This could explain yeast prion cross-seeding and the 'mutation' phenomena using the known structural information.

General Model

How may all these phenomena be brought together? The recent experimental evidence for these emerging concepts now allows a general model for mammalian prions to be proposed (table S1), which accommodates the known phenomena of exponential propagation of infectivity, strain diversity and mutation, transmission barriers, and the uncoupling of infectivity from neurotoxicity, while remaining within the constraint of requiring only a single polypeptide to constitute all strains of infective and toxic species.

Essentially, the phenomena of prion disease pathogenesis can be explained in terms of the kinetics of prion propagation, determined by interplay between prion strain type (dominant PrP Sc polymer and its ensemble) and tissue/host environment (PrP sequence and expression level, modifier genes, and clearance mechanisms) selection of preferred conformers determines transmission barriers. Neurotoxicity is mediated by a PrP species, PrP L , distinct from PrP Sc but catalyzed by it, and occurs when PrP L concentration passes a local toxic threshold. Rapid propagation (with a host-adapted strain and normal or high levels of host PrP C expression) results in severe neurotoxicity and death at strain-specific incubation periods. Slow propagation (after infection across a transmission barrier or with low host PrP C expression) results in low neurotoxicity and prolonged and more variable incubation periods or a persistent carrier state.

The concept of prion strain originated from biological experiments, but at a molecular level there may be quite distinct infectious PrP polymers (PrP Sc types) that cannot be distinguished by transmission studies in inbred laboratory mouse lines. Although in practice, the converse situation of biologically distinct prion strains associated with PrP Sc that cannot be biochemically differentiated by current methods will also be observed, under this general protein-only model such biochemical or biophysical differences in PrP Sc must exist, and the model would predict that differences would be observed with more discriminating molecular methods, challenging the historical primacy of biological classification of prion strains.


AmyPro is a novel, carefully curated database of amyloid precursor proteins and their amyloidogenic sequence regions that aims to provide an up-to-date view of the entire amylome. It contains significantly more amyloid-forming proteins than any of its peers, mainly due to incorporating validated functional amyloids and prion proteins from all kingdoms of life for the first time. AmyPro will be regularly updated, relying not only on data submissions from the research community but also on regular internal updates based on scanning newly published amyloid literature. By storing the most comprehensive list of amyloid fibril-forming proteins published so far in combination with a useful set of features facilitating their efficient analysis, we anticipate AmyPro to become central to amyloid research, and to have major impact on its progress. To achieve this goal we are dedicated to ensure the long-term availability of the database.

In particular, AmyPro has huge potential in helping to elucidate the sequential determinants of amyloid fibril formation. Furthermore, the provided functional classifications might enable refining these sequential determinants according to the biological functions of amyloid fibrils and understanding the functional relevance of their differences. Better definition of the sequence determinants of amyloid fibril formation will also help in understanding and predicting the effects of mutations within amyloidogenic sequence fragments and relate them to the underlying molecular mechanisms, which in turn may enable the development of novel methods for more accurate computational identification of amyloidogenic regions within proteins.

Watch the video: What are paraproteins (May 2022).


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