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  • Reply to: The Prion Hypothesis at Forty: Enlightening or Deceptive?   1 month 1 day ago

    Prions, propagative amyloids, prionoids, prion-like agents...

    This opens a can of worms...I recommend the enlightening paper: "The Prion 2028 round tables (II): Abeta, tau, alpha-synuclein: are they prions, prion-like proteins or what...? (Prion, 2019, 13:41-45) in which my colleague and friend Hasier Eraña summarizes a round table he chaired during the Prion 2018 international prion meeting held in Santiago de Compostela on this subject., with participation of Stanley Prusiner, Claudio Soto, Mathias Jucker and Corinne Lasmezas among other prominent experts, not forgetting the audience. There even was an informal poll on the subject, which, contrary to the predominant opinion of the table members, showed a majority of researchers stating that Amyloid beta, tau etc. are "prion-like agents". 

    In my opinion, one has to stick to the original definition provided by prusiner: prions are infectious agents composed solely of protein. Now, what does "infectious" mean? Is a cancer that one passages from nude mouse to nude mouse an infectious agent? Yes, but only under very articicial circumstances...However, the oral cancer of Tasmanian devils does seem to qualify without restrictions, as it propagates between Tasmanian devils under completely natural circumstances... Is TMV infectious? Yes, but only to tobacco plants...So even the most basic part of the definition may be complicated. In my humble opinion (at least at this moment, I have changed back and forth many times...) to qualify as a prion a protein ensemble must be able to propagate under "relatively" normal conditions, meaning orally, or through an open sore or wound, or iatrogenically, and between wt individuals. This excludes Abeta and tau (unless until recent findings on apparent transmission of Abeta to recipients of contaminated growth hormone, leading to death as a consequence of Alzheimer´s disease are fully confirmed. 

    About the first part of the definition "composed solely of protein", I can attest to the fact (because I do it all the time in my lab) that a mixture of recombinant PrP, dextran and detergent in an inorganic buffer, subject to a simple protocol of agitation, can become infectious. So in my experience prions (protein assemblies that are infectious by themselves) do exist.

    But of course this is a fascinating subject and there are many opinions.  


  • Reply to: The Prion Hypothesis at Forty: Enlightening or Deceptive?   1 month 5 days ago


    I would like to thank Kariem Ezzat and Jesús Requena for their comments and for bringing forward a critical issue that has plagued the prion hypothesis for the last four decades: what exactly are prions? To address this question, the prions need to be clearly defined and differentiated from other protein aggregates.

    When viruses were identified as a distinct group of infectious pathogens at the end of the 19th century, they were defined as novel disease agents that passed through porcelain filters assumed at the time to retain all microbial (i.e., cellular) pathogens [1]. Martinus Beijerinck labeled these ‘filterable pathogens’ with the descriptive name “contagium vivum fluidum”. Later, in the mid-1930s, Wendell Stanley isolated the tobacco mosaic virus, more exactly the virus particles produced by the virus, in a crystalline form and defined viruses as ‘self-replicating proteins’: “Tobacco-mosaic virus is regarded as an autocatalytic protein which, for the present, may be assumed to require the presence of living cells for multiplication” (all quotes in italics; [2]). This definition was abandoned after it was found that the infectious virus particles contained nucleic acids [1]. Two decades later, Andre Lwoff concluded his seminal article “The concept of virus” with the (in)famous quip: “viruses should be considered as viruses because viruses are viruses” [3]. So, should prions be considered as prions because prions are prions?

    Like viruses, transmissible spongiform encephalopathies (TSEs) pathogens were conceptually identified with their transmissible forms — the “proteinaceous infectious particles” labeled “prions” by Stanley Prusiner in 1982 [4]. As emphasized by Prusiner at the time, the definition “does not prejudge the chemical composition of the scrapie prion except to state that it does contain a protein” [5]. Indeed, the new term “prion” was intended to be used without any preconceived claims about its biochemical composition and structure: “To avoid prejudging the structure of these infectious particles, three hypothetical structures for the prion were proposed: (1) proteins surrounding a nucleic acid that encodes them (a virus), (2) proteins surrounding a small noncoding polynucleotide, and (3) a proteinaceous particle devoid of nucleic acid.” [6].

    Three decades later, prions were fundamentally redefined: “Prions are proteins that acquire alternative conformations that become self-propagating” [7]. However, as discussed below, this definition encompasses not only all amyloidogenic proteins but also many other proteins that assemble into ordered oligomeric structures.

    Interestingly, the new definition of prions opened the door for perceiving them as ‘activities’ rather than as ‘physical entities.’ Indeed, as Claudia Scheckel and Adriano Aguzzi pointed out, “Although it is now generally accepted that the prion consists largely of the pathological aggregate of the prion protein, PrPSc, prions are defined as a biological activity rather than a physical entity” [8]. Considering also that the TSE ‘physical entities’ or ‘activities’ presumed to undergo self-replication are apparently distinct from ‘physical entities’ or ‘activities’ implicated in the TSE pathogenic mechanisms (yet to be clearly identified or labelled) [9-12], the definition of prions becomes even more confusing.

    Nevertheless, as mentioned in the essay [13] and the comments above, under certain conditions, all proteins can acquire alternative conformations and assemble into amyloid fibers. Indeed, two decades ago, Christopher Dobson suggested that: “the ability to form amyloid is a generic property of polypeptide chains. This ability can readily be explained by the fact that the intermolecular bonds that stabilize this material involve the peptide backbone, which is common to all proteins” [14]. Therefore, if indeed prions are “proteins that acquire alternative conformations that become self-propagating” [7] then, under certain conditions, all proteins can become prions.

    However, with some exceptions (e.g., secreted/surface components), natural proteins function under physiological conditions and, as Dobson suggested [14], most of them are unlikely to assemble into amyloidogenic structures, unless, as pointed out in the essay [13], they were selected for this propensity in connection with their biological function.

    Interestingly, Peter Lansbury [15] and Dobson [14] proposed a protective function for the mature amyloids formed by the proteins implicated in neurodegenerative diseases: “Like the monomeric folding intermediates discussed above, a β-sheet-containing oligomeric species could bind tightly to any number of cellular targets, triggering, for example, a cytotoxic cascade (see Fig. 2). The smallest intermediate in which the binding site (possibly a β-sheet) is stable would have the greatest specific activity (moles binding site per mole protein). Thus, polymerization would compete with binding and specific activity would decrease as polymerization continued. In fact, the fibril itself actually may be protective; fibrillization would be an efficient way for the cell to sequester potentially toxic protofibrils. This proposal has ramifications for the design of screens for discovery of candidate therapeutic agents, because it suggests that some of the compounds that inhibit fibril formation actually could produce a deleterious effect by causing accumulation of a prefibrillar toxic species” (emphasis added; [15]).

    This statement should resonate now stronger than ever with the field of neurodegenerative diseases, particularly Alzheimer’s disease (AD), as some of the putative therapeutic agents interfere with the formation of the plaques and tangles. Nevertheless, the hypothesis proposed by Lansbury and Dobson was advanced in the context of the protein misfolding dogma and the prion hypothesis, in which the assembly of PrP, Aβ, tau, α-Syn, and TDP-43 into various oligomeric/fibrous aggregates was considered an accidental event not related to their biological function. Therefore, it was difficult to envision the self-assembly of these proteins into mature amyloids as a selected adaptive feature. In the innate immunity hypothesis, the formation of diverse oligomeric innate immunity complexes (IICs) with putative toxic properties explains, or even entails, the evolution of regulatory and protective mechanisms, such as their sequestration into inert amyloids [13, 16]. Thus, in this hypothesis, the protective function of amyloids is rooted in a compelling evolutionary rationale.

    The list of functional amyloids is growing [17-23], and there is strong evidence that PrP, Aβ, tau, α-Syn, and TDP-43 are members of the innate immune system (discussed in [13, 16]). However, as pointed out in the comments, several proteins with well-defined non-immunological functions, such as insulin, transition into amyloidogenic states under physiological, albeit stressful, conditions. Likely, the propensity of insulin to form amyloids is related to its innate property to assemble into functional ‘storage oligomers,’ akin to the genuine hormone storage amyloids (e.g., [17]), whose relatively inert amyloid status represents an evolutionary adaptive feature.

    As mentioned above, even some non-amyloidogenic proteins apparently “acquire alternative conformations that become self-propagating” under physiological conditions and, therefore, fulfill the new definition of prions. Indeed, some of the most fascinating innate immunity proteins, such as MAVS and ASC, assemble into antiviral innate immunity complexes (i.e., IICs) that amplify and transduce pathogen-associated signals to downstream effector pathways. Given that the assembly of these proteins into IICs is clearly related to their biological function, their classification as “gain-of-function prions” [24] adds another confusing dimension to the prion hypothesis. Clearly, the assembly of MAVS and ASC into IICs is NOT a “gain-of-function”, but their evolutionary selected biological function, which makes them intriguing models for the putative function of PrP, Aβ, tau, α-Syn, and TDP-43 in innate immunity.

    Are there other more mundane proteins that could be defined as prions under their new definition? Consider, for example, the following excerpt from a decade-old Alzforum article “Mice Tell Tale of Tau Transmission, Alzheimer’s Progression”, in which Bradley Hyman fails to see a fundamental difference between the proteins labeled prions, or prion-like, and more ordinary proteins, such as hemoglobin: “While researchers believe that misfolded, toxic forms of tau can corrupt normal tau molecules in a process called templated protein misfolding, “the notion that there is templated protein alteration is not the same as an infection,” Hyman told ARF. He noted that any protein in the body that forms an oligomer undergoes templated folding. This would include many proteins, such as, for example, hemoglobin” (quotation from [25]).

    There is no stronger argument for the prion paradigm than the concept of templated protein (mis)folding, which is foundational for explaining the ‘strains’ phenomenon associated with the TSEs and other neurodegenerative diseases, including AD, PD, and ALS. The existence of TSE strains with distinct disease phenotypes was used for decades as the primary argument for the viral etiology of TSEs, and against the protein-only paradigm and prion hypothesis. Remarkably, the ‘strains’ phenomenon is now used as one of the main arguments for the existence of prions as distinct biological entities carrying ‘hereditary information,’ which presumably differentiate them from other amyloidogenic proteins.

    Although the prions’ so-called hereditary information, conferring the prion strains their propagation and clinicopathological specificity, was thought for decades to be encoded in distinct misfolded PrP conformations, direct evidence supporting this presumption has only been reported recently [26-28] . Nevertheless, as exciting as the cryogenic electron microscopy (cryo-EM) studies providing this evidence are, it is not clear at this time if the conformational differences between the strains (e.g., 263K vs. RML prions) were dictated by sequence differences in the parental PrP molecules versus conformational templating. Additionally, it is not known whether non-PrP factors participated in the assembly of the ex vivo fibrils used in these cryo-EM studies; the apparent participation of essential cofactors, including RNA molecules, in the formation of infectious prions has been well documented ([29]; for putative roles of nucleic acids in the ‘life cycle’ of amyloidogenic pathogens see [30-34]). More importantly, though, all these structural findings must be evaluated in the context of the well-established but rarely articulated fact that the TSEs, as well as the entities called prions (whatever they are), can arise spontaneously in the absence of prion-based hereditary information or templating activity [35, 36]. In the context of the innate immunity model, the ‘hereditary information’ and ‘templating activity’ of prions represent a conceptual mirage rooted in the misleading protein misfolding dogma and the prion hypothesis [13, 16].

    The generation of synthetic prions from recombinant PrP has been regarded as the ultimate proof for the prion hypothesis and the protein-only paradigm. The results of these studies have been mixed and often confusing, not least because of the problems with defining prions, as recently articulated by scientists from the MRC Prion Unit at UCL, Institute of Prion Diseases: “After all, to be able to determine if a synthetic prion has been made, one must first know what a prion is or, at the very least, what a prion is not” (emphasis added; [37]). Clearly, defining prions is not a frivolous academic undertaking tangential to the experimental work, but a foundational rationale for planning, conducting, and making sense of the laboratory studies. At this time, though, it is reasonable to assume that, after forty years, the definition of prions will continue to ‘shift and drift,’ to use a recent take on the ‘science of prions’ [38]. As proposed next, a reasonable solution might be to reevaluate the relevance of the prion hypothesis and prion paradigm for explaining the etiology of TSEs and other neurodegenerative diseases, and to reconsider the need for defining prions.

    As outlined in the essay, the prion hypothesis was formulated in context of the century-old, misleading dogma of viruses as virus particles [13, 16, 34]. Virus particles are highly specialized structures produced by some, but not all, viruses for their transmission to new host cells; therefore, based this fact alone, identifying viruses with the virus particles and defining them based on their physical and biochemical properties is flawed. Viruses pass in their life cycle through multiple stages, each with distinct physical characteristics, biochemical composition, and biological properties; thus, an integrated sum of all these stages and their characteristics define viruses [39, 40]. Similarly, identifying the TSEs pathogens physically and conceptually with their transmissible entities is misleading and, by analogy with to the new perspective on viruses, the ‘TSE pathogens’ should integrate all aspects of their ‘life cycle’ or more appropriately, their ‘amyloidogenic cycle.’

    As Kariem Ezzat emphasized and as Jesús Requena pragmatically narrated in their comments: “I think that the experimental evidence supporting that PrPSc prions facilitate conversion of PrPC to PrPSc is overwhelming. And there is nothing strange about it: it happens with all seeded amyloid conversions. Incubate any protein under denaturing conditions and slightly acidic pH at 37C and, as Dobson has shown, it will eventually adopt an amyloid conformation; repeat the experiment adding a bit of your pre-formed amyloid as a seed, and the process will be much shorter. I do not see anything unusual there”.  I completely agree. There is nothing fundamentally unusual about the assembly and aggregation process of PrP, Aβ, tau, α-Syn, and TDP-43 into oligomeric structures and amyloid fibers that would differentiate them from amyloidogenic cycles that all proteins can enter, albeit very few under physiological conditions. And if that’s the case, there is no need for the prion hypothesis, for the prion paradigm, or for defining prions.


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  • Reply to: Protecting Progress: Communicating and Using Dementia Risk Evidence   2 months 5 days ago

    Washington post has a series of related articles as well on this topic

    Laurie McGinley discusses blood tests

    Blood tests

    Daniel Gilbert discusses an amyloid reducing drug, lecanumab

  • Reply to: The Prion Hypothesis at Forty: Enlightening or Deceptive?   3 months 2 days ago

    I find the possibility that PrPC is part of the capsid, or protein component in general of a virus, or that it is part of the toolkit of innate immunity to be fascinating. I think they are possibilities that deserve attention and research. On the other hand, I do not think that any of these possibilities necessarily contradicts or is incompatible with the prion proposal. Let me provide an example: the origin of mitochondria is aerobic bacteria that established a symbiotic relation with ancestral eukaryotic cells. There is no question about that. However, they are also organules, as much as lysosomes, peroxysomes or the Golgi apparatus are. I think that the experimental evidence supporting that PrPSc prions facilitate conversion of PrPC to PrPSc is overwhelming. And there is nothing strange about it: it happens with all seeded amyloid conversions. Incubate any protein under denaturing conditions and slightly acidic pH at 37C and, as Dobson has shown, it will eventually adopt an amyloid conformation; repeat the experiment adding a bit of your pre-formed amyloid as a seed, and the process will be much shorter. I do not see anything unusual there. 

  • Reply to: The Prion Hypothesis at Forty: Enlightening or Deceptive?   3 months 5 days ago

    Many thanks for sharing your interesting blog Dr. Bandea. I agree with many things, especially the confusing, mechanistically-unsubstantiated aspects of the prion hypothesis. Regarding the innate immune properties of amyloids, since any protein can form amyloids, I’m not sure if it is a functional property. Proteins such as insulin or myoglobin, which have very specific, non-immune functions, can still form amyloids, and so can any other peptide sequence. That’s why I subscribe to the “generic hypothesis”(coined by the late Chris Dobson), that amyloids are a generic conformation of proteins that they adopt under certain conditions. We are going to publish a book chapter soon where we postulate that a simple extension of the Anfinsen hypothesis of protein folding to supersaturated conditions can fully explain the amyloid phenomenon without the need for the assumptions of the prion hypothesis. We argue that proteins possess two thermodynamically stable conformations and possess the necessary information to adopt either of them:

    1.    The native conformation, which is thermodynamically favorable under sub-supersaturation conditions and is dependent on the primary sequence and specific side-chain interactions.

    2.   The cross-β (amyloid) conformation, which is thermodynamically favorable under supersaturated conditions and is dependent on generic intermolecular backbone interaction facilitated by the molecular proximity created under supersaturation.

    The concentration and the availability of nucleation catalysts are the factors that decide which conformation will be adopted. But since amyloids are generic (depend on backbone interactions and the characteristic protein side chains are buried within the cross-beta architecture) and their growth is uncontrolled, I believe mechanisms (such as chaperones, and proteasomes) have evolved to prevent their formation and not the other way round. That’s probably why they are mostly associated with disease when these mechanisms fail, or when concentration is pathologically increased (gene duplication), or when nucleation catalysts invade the microenvironment (viruses, other infections). 

  • Reply to: APOE4 Copy Number-Dependent Proteomic Changes in the Cerebrospinal Fluid.   8 months 1 week ago

    I vote for this paper.