Sanders DW, Kaufman SK, DeVos SL, Sharma AM, Mirbaha H, Li A, Barker SJ, Foley AC, Thorpe JR, Serpell LC, Miller TM, Grinberg LT, Seeley WW, Diamond MI. Distinct tau prion strains propagate in cells and mice and define different tauopathies. Neuron. 2014 Jun 18;82(6):1271-88. Epub 2014 May 22 PubMed.

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  1. This is a very carefully done and exciting study that convincingly demonstrates the existence of tau conformers ("strains") in living systems. In vivo strains have been suggested previously for tau (e.g., Clavaguera et al., 2013), synuclein (e.g., Guo et al., 2013), and Aβ (e.g., Lu et al., 2013; Heilbronner et al., 2013; see also LeVine and Walker, 2010, for review), but the previous studies have been largely suggestive rather than providing proof of the strain concept.  I am not sure whether this most recent study from the Diamond lab will settle the debate about whether one should call pathogenic tau seeds "prions" or not (and in my view, this debate is no longer fruitful); rather, we should build on these exciting new tau results and the overall recent insights that not only prions, but also Aβ, tau, and synuclein can form self-propagating pathogenic aggregates that in turn suggest therapeutic and diagnostic targets (for review see Jucker and Walker, 2013).

    References:

    Clavaguera F, Akatsu H, Fraser G, Crowther RA, Frank S, Hench J, Probst A, Winkler DT, Reichwald J, Staufenbiel M, Ghetti B, Goedert M, Tolnay M. Brain homogenates from human tauopathies induce tau inclusions in mouse brain. Proc Natl Acad Sci U S A. 2013 Jun 4;110(23):9535-40. PubMed.

    Guo JL, Covell DJ, Daniels JP, Iba M, Stieber A, Zhang B, Riddle DM, Kwong LK, Xu Y, Trojanowski JQ, Lee VM. Distinct α-synuclein strains differentially promote tau inclusions in neurons. Cell. 2013 Jul 3;154(1):103-17. PubMed.

    Lu JX, Qiang W, Yau WM, Schwieters CD, Meredith SC, Tycko R. Molecular Structure of β-Amyloid Fibrils in Alzheimer's Disease Brain Tissue. Cell. 2013 Sep 12;154(6):1257-68. PubMed.

    Heilbronner G, Eisele YS, Langer F, Kaeser SA, Novotny R, Nagarathinam A, Aslund A, Hammarström P, Nilsson KP, Jucker M. Seeded strain-like transmission of β-amyloid morphotypes in APP transgenic mice. EMBO Rep. 2013 Oct 30;14(11):1017-22. PubMed.

    Levine H, Walker LC. Molecular polymorphism of Abeta in Alzheimer's disease. Neurobiol Aging. 2010 Apr;31(4):542-8. PubMed.

    Jucker M, Walker LC. Self-propagation of pathogenic protein aggregates in neurodegenerative diseases. Nature. 2013 Sep 5;501(7465):45-51. PubMed.

    View all comments by Mathias Jucker

  2. These thorough and elegant studies are the strongest evidence yet that seeds of tau protein behave like prions. They compellingly reinforce the prion concept as one of the most important pathogenic principles of our time. But since a prion is defined as an infectious particle, I am uncomfortable with the use of the word to describe agents of non-infectious diseases (*see definition below). On the other hand, the word "prion" is useful, concise, and undoubtedly here to stay. Perhaps, in the broader context of prionology, we should keep the word and agree on a more comprehensive, accurate, and less disquieting definition (proteinaceous inductive particle?).

    * infectious (adjective): 1. Of a disease or disease-causing organism) liable to be transmitted to people, organisms, etc. through the environment.

    (From the Oxford Dictionaries online)

    View all comments by Lary Walker

  3. I agree with Mathias Jucker that the current debate about whether we should refer to protein amyloids that cause disease as “prions” or “prion-like” or some other word is not fruitful. One could theoretically use “infectious” as a critical criterion to define a bacterium, but that is obviously not very useful, or even accurate. For example, consider non-pathogenic E. coli that reside in the gut. If such bacteria were inoculated artificially into an inappropriate location, e.g., the brain or blood, they would produce disease that is “transmissible” through transfer of biological fluids. Yet nobody would consider this important, and it would not engender any interest from a public health standpoint. Similarly, work by our lab and others involve inoculation of pure protein into animal hosts that are primed to develop pathology, and this pathology is “transmissible” from animal to animal. Unless human tau were delivered in a similar fashion into patients, it seems highly unlikely that it would cause any problems in the general population. Indeed, were it not for relatively extreme human activities—cannibalism, brain surgery, tissue transplantation, feeding offal to livestock—human prion disease would not be known to be infectious, and instead would look like every other amyloidosis, with sporadic and genetic causes (and this is of course how virtually all prion cases present).

    With that said, I think the field would be remiss in dismissing the possible infectious nature of protein amyloids simply because there is no known evidence of interperson transmission. In theory this could happen, and we should be aware of it as a possibility. We do a disservice by drawing an artificial line between PrP prions and other types of prions based simply on known infectivity, when there are so many other critical biological similarities.

    View all comments by Marc Diamond

  4. This study is an elegant demonstration of tau strains, which extends earlier work that demonstrated strains of tau using human brain lysates (Claveguera et al., 2013). Indeed, Sanders et al. add to the growing body of literature demonstrating that other non-prion neurodegenerative disease proteins, such as α-synuclein and Aβ, can exist as different strains of disease proteins (Guo et al., 2013; Heilbronner et al., 2013; Lu et al., 2013). However, contrary to the authors’ assertions, the existence of pathological strains of tau does not establish that these pathological tau proteins are prions. Indeed, neither pathological tau nor pathological species of α-synuclein and Aβ can be termed prions because they are neither infectious nor zoonoses in the way prion diseases are. The very name prion was coined by S. Prusiner in 1982 when he renamed the scrapie agent a prion (Prusiner, 19821). Notably, the scrapie agent is the extensively studied infectious entity responsible for a highly infectious neurodegenerative disease in sheep. By renaming the scrapie agent a prion, Prusiner defined the prion as a "proteinacious infectious particle.” (“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.”)

    Accordingly, infectivity is one of the essential components of the definition of prions, and this is the definition that is found repeatedly in online dictionaries and in Google with no mention of strains being essential to the definition of prions. Infectious spread of prions is very real and not just through iatrogenic means, but through the food supply, which justifies categorizing infectious prion diseases as zoonoses. This was dramatically evidenced by the spread of prion disease from cattle to humans, which was termed “Mad Cow” disease (Sikorska et al., 2012). Moreover, in the original population of the Foré linguistic group of Papua New Guinea in whom person-to-person spread of the infectious prion disease kuru occurred through recurrent exposure to the CNS tissues of afflicted individuals, there were never any reports that AD, PD, or other non-prion neurodegenerative tauopathies, synucleinopathies, or Aβopathies were spread by ritual cannibalism, which is thought to be the basis for this person-to-person spread of kuru. This is despite the fact that pathological tau begins to deposit in the CNS as early as the second decade of life, followed soon thereafter by Aβ. Moreover there are no epidemiological data to support the notion that there is infectious spread of AD, PD, or other tauopathies, Aβopathies, and synucleinopathies through blood transfusions, organ transplants or other means. Indeed, we found no evidence of the spread of any of these diseases in middle-aged and older individuals who, as children, were treated between 1965 to 1985 with daily injections of human growth hormone extracted from postmortem human pituitaries, and who were longitudinally followed, despite the fact that 24 cases of prion disease occurred in this cohort of more than 7,000 individuals (Irwin et al., 2013). 

    Thus, despite the fact that infectious prion diseases are clearly zoonoses and there is no evidence that AD, PD, and related synucleinopathies, Aβopathies, and tauopathies are infections or zoonotic diseases, the starker contrast between prions and non-prion neurodegenererative disease proteins with respect to infectivity comes not from human data, but from data on the very high prevalence of readily transmissible or infectious prion diseases in sheep, cattle, moose, elk, and other animals for which there is just no counterpart for tauopathies, Aβopathies, or synucleinopathies. Indeed, the estimated economic costs incurred by responding to bovine spongiform encephalopathy in the EU between November 2000 and December 2010 ranged between €1,847 million and €2,094 million (Probst et al., 2013). Nothing comparable has occurred for tauopathies, Aβopathies, or synucleinopathies in livestock, nor is anything likely to occur, because there is no reservoir of infectious tauopathies, Aβopathies, or synucleinopathies in livestock or other mammals. 

    Therefore, for those who agree with Stan Prusiner that a prion is a “proteinacious infectious particle,” the burden of proof is on them—if they wish to call tau, α-synuclein, and Aβ prions—to demonstrate the infectivity of these neurodegenerative disease proteins in humans, and, more importantly, I think, to demonstrate the existence of reservoirs of infectious tauopathies, synucleinopathies, and Aβopathies affecting thousands or perhaps hundreds of thousands of sheep, deer, elk or other animals in the wild as is clearly the case for prion diseases, which in part contributed to Prusiner’s definition of prions as proteinaceous infectious particles. 

    1 For clarity, the abstract of the paper by Prusiner introducing the term prion is here in this footnote. Abstract: After infection and a prolonged incubation period, the scrapie agent causes a degenerative disease of the central nervous system in sheep and goats. Six lines of evidence including sensitivity to proteases demonstrate that this agent contains a protein that is required for infectivity. Although the scrapie agent is irreversibly inactivated by alkali, five procedures with more specificity for modifying nucleic acids failed to cause inactivation. The agent shows heterogeneity with respect to size, apparently a result of its hydrophobicity; the smallest form may have a molecular weight of 50,000 or less. 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. Knowledge of the scrapie agent structure may have significance for understanding the causes of several degenerative diseases.

    References:

    Clavaguera F, Bolmont T, Crowther RA, Abramowski D, Frank S, Probst A, Fraser G, Stalder AK, Beibel M, Staufenbiel M, Jucker M, Goedert M, Tolnay M. Transmission and spreading of tauopathy in transgenic mouse brain. Nat Cell Biol. 2009 Jul;11(7):909-13. PubMed.

    Guo JL, Covell DJ, Daniels JP, Iba M, Stieber A, Zhang B, Riddle DM, Kwong LK, Xu Y, Trojanowski JQ, Lee VM. Distinct α-synuclein strains differentially promote tau inclusions in neurons. Cell. 2013 Jul 3;154(1):103-17. PubMed.

    Heilbronner G, Eisele YS, Langer F, Kaeser SA, Novotny R, Nagarathinam A, Aslund A, Hammarström P, Nilsson KP, Jucker M. Seeded strain-like transmission of β-amyloid morphotypes in APP transgenic mice. EMBO Rep. 2013 Oct 30;14(11):1017-22. PubMed.

    Lu JX, Qiang W, Yau WM, Schwieters CD, Meredith SC, Tycko R. Molecular Structure of β-Amyloid Fibrils in Alzheimer's Disease Brain Tissue. Cell. 2013 Sep 12;154(6):1257-68. PubMed.

    Prusiner SB. Novel proteinaceous infectious particles cause scrapie. Science. 1982 Apr 9;216(4542):136-44. PubMed.

    Sikorska B, Liberski PP. Human prion diseases: from Kuru to variant Creutzfeldt-Jakob disease. Subcell Biochem. 2012;65:457-96. PubMed.

    Irwin DJ, Abrams JY, Schonberger LB, Leschek EW, Mills JL, Lee VM, Trojanowski JQ. Evaluation of potential infectivity of Alzheimer and Parkinson disease proteins in recipients of cadaver-derived human growth hormone. JAMA Neurol. 2013 Apr;70(4):462-8. PubMed.

    Probst C, Gethmann JM, Heuser R, Niemann H, Conraths FJ. Direct costs of bovine spongiform encephalopathy control measures in Germany. Zoonoses Public Health. 2013 Dec;60(8):577-95. Epub 2013 Jan 10 PubMed.

    View all comments by John Trojanowski

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