View source for Prion

{{Short description|Pathogenic type of misfolded protein}}
{{About||the bird|Prion (bird)|the theoretical subatomic particle|Preon}}
{{Distinguish|Major prion protein}}
{{Good article}}
{{use mdy dates|date=September 2022}}<!--Looks like the preference to me.-->
{{cs1 config|name-list-style=vanc|display-authors=6}}{{Use American English|date=March 2026}}

{{Infobox medical condition
| name = Prion
| image = PDB 6DU9.png
| caption = 3D structure of [[major prion protein]]
| specialty = [[Infectious diseases (medical specialty)|Infectious diseases]]
| pronounce = {{IPAc-en|audio=Pronunciation prion.ogg|ˈ|p|r|iː|ɒ|n}}, {{IPAc-en|ˈ|p|r|aɪ|ɒ|n}}<ref>{{cite web |title=English pronunciation of prion |url=https://dictionary.cambridge.org/pronunciation/english/prion |website=Cambridge Dictionary |publisher=Cambridge University Press |access-date=30 March 2020 |archive-url=https://web.archive.org/web/20170424075831/http://dictionary.cambridge.org/pronunciation/english/prion |archive-date=24 April 2017 |url-status=live}}</ref><ref>{{cite web |title=Definition of Prion |year=2021 |website=[[Dictionary.com]] |publisher=Random House, Inc. |at=Definition 2 of 2 |url=https://www.dictionary.com/browse/prion#luna-section |access-date=2021-09-12 |url-status=live |archive-date=2021-09-12 |archive-url=https://web.archive.org/web/20210912092658/https://www.dictionary.com/browse/prion#luna-section}}</ref>
}}

A '''prion''' ({{IPAc-en|audio=Pronunciation prion.ogg|ˈ|p|r|iː|ɒ|n}}) is a [[Proteinopathy|misfolded protein]]<nowiki/> that induces [[Protein folding|folding]] problems in normal variants of the same protein, leading to [[cellular death]]. Prions are responsible for [[prion disease]]s, which are fatal and transmissible [[neurodegenerative disease]]s affecting animals, including humans. These proteins can misfold sporadically, due to genetic mutations, or through exposure to an already misfolded protein, leading to an abnormal [[Protein tertiary structure|three-dimensional structure]] that can propagate misfolding in other proteins.<ref>{{cite book | vauthors = Kumar V |title=Robbins & Cotran Pathologic Basis of Disease |year=2021 |edition=10th}}</ref>

The term ''prion'' derives from "proteinaceous infectious particle". Unlike other [[Pathogen|infectious agents]] such as [[Virus|viruses]], [[bacteria]], and [[Fungus|fungi]], prions do not contain [[nucleic acid]]s ([[DNA]] or [[RNA]]). Prions are primarily twisted [[Protein isoform|isoforms]] of the [[major prion protein]] (PrP), a naturally occurring protein with an uncertain function. They are the hypothesized cause of various diseases, including [[scrapie]] in sheep, [[chronic wasting disease]] (CWD) in deer, [[bovine spongiform encephalopathy]] (BSE) in cattle (mad cow disease), and [[Creutzfeldt–Jakob disease]] (CJD) in humans.

All known prion diseases in [[mammal]]s affect the structure of the [[brain]] or other [[neuron|neural]] tissues. These diseases are progressive, have no known effective treatment, and are invariably fatal. Most prion diseases were thought to be caused by PrP until 2015 when a prion form of [[alpha-synuclein]] was linked to [[multiple system atrophy]] (MSA). Misfolded proteins are also linked to other neurodegenerative diseases like [[Alzheimer's disease]], [[Parkinson's disease]], and [[amyotrophic lateral sclerosis]] (ALS), which have been shown to originate and progress by a prion-like mechanism.<ref name="WalkJuck 2015">{{cite journal | vauthors=Walker LC, Jucker M | date=2015 | title=Neurodegenerative diseases: Expanding the prion concept | journal=Annual Review of Neuroscience | volume=38 | pages=87–103| doi=10.1146/annurev-neuro-071714-033828 | pmc=4803040 | pmid=25840008}}</ref><ref name="Olanow">{{cite journal | vauthors = Olanow CW, Brundin P | title = Parkinson's disease and alpha synuclein: is Parkinson's disease a prion-like disorder? | journal = Movement Disorders | volume = 28 | issue = 1 | pages = 31–40 | date = January 2013 | pmid = 23390095 | doi = 10.1002/mds.25373 | s2cid = 38287298 }}</ref><ref name="pmid19242475">{{cite journal | vauthors = Laurén J, Gimbel DA, Nygaard HB, Gilbert JW, Strittmatter SM | title = Cellular prion protein mediates impairment of synaptic plasticity by amyloid-beta oligomers | journal = Nature | volume = 457 | issue = 7233 | pages = 1128–32 | date = February 2009 | pmid = 19242475 | pmc = 2748841 | doi = 10.1038/nature07761 | bibcode = 2009Natur.457.1128L }}</ref>

Prions are a type of [[intrinsically disordered protein]] that continuously changes conformation unless bound to a specific partner, such as another protein. Once a prion binds to another in the same conformation, it stabilizes and can form a [[fibril]], leading to abnormal protein aggregates called [[amyloids]]. These amyloids accumulate in infected tissue, causing damage and cell death.<ref>{{cite journal | vauthors = Dobson CM | title = The structural basis of protein folding and its links with human disease | journal = Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences | volume = 356 | issue = 1406 | pages = 133–145 | date = February 2001 | pmid = 11260793 | pmc = 1088418 | doi = 10.1098/rstb.2000.0758 }}</ref> The structural stability of prions makes them resistant to [[denaturation (biochemistry)|denaturation]] by chemical or physical agents, complicating disposal and containment, and raising concerns about (physician caused) [[Iatrogenesis|iatrogenic spread]]  through medical instruments.

== Etymology and pronunciation ==
The word ''prion'', coined in 1982 by [[Stanley B. Prusiner]], is derived from '''pr'''otein and infect'''ion''', hence '''prion'''.<ref name="Prusiner82" /> It is short for "proteinaceous infectious particle",<ref name=pmid26324905>{{cite journal | vauthors = Prusiner SB, Woerman AL, Mordes DA, Watts JC, Rampersaud R, Berry DB, Patel S, Oehler A, Lowe JK, Kravitz SN, Geschwind DH, Glidden DV, Halliday GM, Middleton LT, Gentleman SM, Grinberg LT, Giles K | title = Evidence for α-synuclein prions causing multiple system atrophy in humans with parkinsonism | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 112 | issue = 38 | pages = E5308–17 | date = September 2015 | pmid = 26324905 | pmc = 4586853 | doi = 10.1073/pnas.1514475112 | doi-access = free | bibcode = 2015PNAS..112E5308P }}<br />Lay summary: {{cite web | vauthors = Makin S |title=A Red Flag for a Neurodegenerative Disease That May Be Transmissible |url=http://www.scientificamerican.com/article/a-red-flag-for-a-neurodegenerative-disease-that-may-be-transmissible/ |date=September 1, 2015 |website=Scientific American}}</ref> in reference to its ability to self-propagate and transmit its conformation to other proteins.<ref name="Nobel">{{cite web |title=Stanley B. Prusiner – Autobiography |url=http://nobelprize.org/nobel_prizes/medicine/laureates/1997/prusiner-autobio.html |publisher=NobelPrize.org |access-date=2007-01-02 |archive-date=2013-06-16 |archive-url=https://web.archive.org/web/20130616122714/http://www.nobelprize.org/nobel_prizes/medicine/laureates/1997/prusiner-autobio.html |url-status=live}}</ref> Its main pronunciation is {{IPAc-en|audio=Pronunciation prion.ogg|ˈ|p|r|iː|ɒ|n}},<ref>{{cite journal | vauthors = Schonberger LB, Schonberger RB | title = Etymologia: prion | journal = Emerging Infectious Diseases | volume = 18 | issue = 6 | pages = 1030–1 | date = June 2012 | pmid = 22607731 | pmc = 3381685 | doi = 10.3201/eid1806.120271 }}</ref><ref name="Dorlands">{{cite web |title=Dorland's Illustrated Medical Dictionary |publisher=Elsevier |url=http://dorlands.com/ |access-date=2016-07-22 |url-access=subscription |url-status=dead |archive-date=2014-01-11 |archive-url=https://web.archive.org/web/20140111192614/http://dorlands.com/}}</ref><ref name="MWU">{{cite web |title=Merriam-Webster's Unabridged Dictionary |publisher=Merriam-Webster |url=http://unabridged.merriam-webster.com/unabridged/ |access-date=2016-07-22 |archive-date=2020-05-25 |archive-url=https://web.archive.org/web/20200525084504/https://unabridged.merriam-webster.com/subscriber/login?redirect_to=%2Funabridged%2F |url-status=dead |url-access=subscription}}</ref> although {{IPAc-en|ˈ|p|r|aɪ|ɒ|n}}, as the [[homograph]]ic name of [[prion (bird)|the bird]] (prions or whalebirds) is pronounced,<ref name="MWU"/> is also heard.<ref name="AHD">{{cite web |title=The American Heritage Dictionary of the English Language |publisher=Houghton Mifflin Harcourt |url=https://ahdictionary.com/ |access-date=2016-07-22 |url-status=dead |archive-date=2015-09-25 |archive-url=https://web.archive.org/web/20150925104737/https://ahdictionary.com/}}</ref> In his 1982 paper introducing the term, Prusiner specified that it is "pronounced ''pree-on''".<ref name=Prusiner82/>

== Prion protein ==
{{See also|Major prion protein}}

=== Structure ===
{{Further|Major prion protein#Structure}}

Prions consist of a misfolded form of [[major prion protein]] (PrP), a protein that is a natural part of the bodies of humans and other animals. The PrP found in infectious prions has a different [[Protein structure|structure]] and is resistant to [[protease]]s, the enzymes in the body that can normally break down proteins. The normal form of the protein is called PrP<sup>C</sup>, while the infectious form is called PrP<sup>Sc</sup>&nbsp;– the ''C'' refers to 'cellular' PrP, while the ''Sc'' refers to '[[scrapie]]', the prototypic prion disease, occurring in sheep.<ref name="sci5621">{{cite journal | vauthors = Priola SA, Chesebro B, Caughey B | title = Biomedicine. A view from the top--prion diseases from 10,000 feet | journal = Science | volume = 300 | issue = 5621 | pages = 917–9 | date = May 2003 | pmid = 12738843 | doi = 10.1126/science.1085920 | url = https://zenodo.org/record/1230830 | access-date = 2020-07-28 | url-status = live | s2cid = 38459669 | archive-url = https://web.archive.org/web/20200728140633/https://zenodo.org/record/1230830 | archive-date = 2020-07-28 }}</ref> PrP can also be induced to fold into other more-or-less well-defined isoforms in vitro; although their relationships to the form(s) that are pathogenic in vivo is often unclear, high-resolution structural analyses have begun to reveal structural features that correlate with prion infectivity.<ref>{{cite journal | vauthors = Artikis E, Kraus A, Caughey B | title = Structural biology of ex vivo mammalian prions | journal = The Journal of Biological Chemistry | volume = 298 | issue = 8 | article-number = 102181 | date = August 2022 | pmid = 35752366 | pmc = 9293645 | doi = 10.1016/j.jbc.2022.102181 | doi-access = free }}</ref>

==== PrP<sup>C</sup> ====
PrP<sup>C</sup> is a normal protein found on the [[cell membrane|membranes]] of [[cell (biology)|cells]], "including several blood components of which [[platelets]] constitute the largest reservoir in humans".<ref name="robertson06">{{cite journal | vauthors = Robertson C, Booth SA, Beniac DR, Coulthart MB, Booth TF, McNicol A | title = Cellular prion protein is released on exosomes from activated platelets | journal = Blood | volume = 107 | issue = 10 | pages = 3907–11 | date = May 2006 | pmid = 16434486 | doi = 10.1182/blood-2005-02-0802 | s2cid = 34141310 | doi-access = free }}</ref> It has 209 [[amino acid]]s (in humans), one [[disulfide bond]], a molecular mass of {{val|35|–|36|ul=kDa}} and a mainly [[alpha helix|alpha-helical]] structure.<ref>{{cite journal | vauthors = Riek R, Hornemann S, Wider G, Glockshuber R, Wüthrich K | title = NMR characterization of the full-length recombinant murine prion protein, mPrP(23-231) | journal = FEBS Letters | volume = 413 | issue = 2 | pages = 282–8 | date = August 1997 | pmid = 9280298 | doi = 10.1016/S0014-5793(97)00920-4 | s2cid = 39791520 | bibcode = 1997FEBSL.413..282R | url = https://www.zora.uzh.ch/id/eprint/191727/1/S0014-5793%2897%2900920-4.pdf }}</ref><ref>{{cite journal | vauthors = Donne DG, Viles JH, Groth D, Mehlhorn I, James TL, Cohen FE, Prusiner SB, Wright PE, Dyson HJ | title = Structure of the recombinant full-length hamster prion protein PrP(29-231): the N terminus is highly flexible | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 94 | issue = 25 | pages = 13452–7 | date = December 1997 | pmid = 9391046 | pmc = 28326 | doi = 10.1073/pnas.94.25.13452 | doi-access = free | bibcode = 1997PNAS...9413452D }}</ref> Several [[Protein topology|topological]] forms exist; one cell surface form that is anchored via [[glycolipid]], and two [[transmembrane]] forms.<ref>{{cite journal | vauthors = Hegde RS, Mastrianni JA, Scott MR, DeFea KA, Tremblay P, Torchia M, DeArmond SJ, Prusiner SB, Lingappa VR | title = A transmembrane form of the prion protein in neurodegenerative disease | journal = Science | volume = 279 | issue = 5352 | pages = 827–834 | date = February 1998 | pmid = 9452375 | doi = 10.1126/science.279.5352.827 | url = http://pdfs.semanticscholar.org/4320/9efc152784dbc7f0b9a1300d0ec9be602a2c.pdf | url-status = dead | s2cid = 20176119 | bibcode = 1998Sci...279..827H | archive-url = https://web.archive.org/web/20190223062543/http://pdfs.semanticscholar.org/4320/9efc152784dbc7f0b9a1300d0ec9be602a2c.pdf | archive-date = 2019-02-23 }}</ref> The normal protein is not sedimentable; meaning that it cannot be separated by [[Laboratory centrifuge|centrifuging techniques]].<ref name=Krull>{{cite book | vauthors = Carp RI, Kascap RJ | chapter = Taking aim at the transmissible spongiform encephalopathie's infectious agents | veditors = Krull IS, Nunnally BK | title = Prions and mad cow disease | publisher = Marcel Dekker | location = New York | year = 2004 | page = 6 | isbn = 978-0-8247-4083-2 | chapter-url = https://books.google.com/books?id=WjeuaHopV5UC&pg=PA6 | access-date = 2020-06-02 | archive-date = 2020-08-20 | archive-url = https://web.archive.org/web/20200820011006/https://books.google.com/books?id=WjeuaHopV5UC&pg=PA6 | url-status = live }}</ref> It has a complex [[Protein function|function]], which continues to be investigated. PrP<sup>C</sup> [[Chemical bond|binds]] [[copper]](II) [[ion]]s (those in a +2 [[oxidation state]]) with [[high affinity]].<ref>{{cite journal | vauthors = Brown DR, Qin K, Herms JW, Madlung A, Manson J, Strome R, Fraser PE, Kruck T, von Bohlen A, Schulz-Schaeffer W, Giese A, Westaway D, Kretzschmar H | title = The cellular prion protein binds copper in vivo | journal = Nature | volume = 390 | issue = 6661 | pages = 684–7 | year = 1997 | pmid = 9414160 | doi = 10.1038/37783 | s2cid = 4388803 | bibcode = 1997Natur.390..684B }}</ref> This property is supposed to play a role in PrP<sup>C</sup>'s [[anti-oxidative]] properties via reversible [[oxidation]] of the [[Protein structure|N-terminal's]] [[methionine]] residues into [[sulfoxide]].<ref>{{cite journal |last1=Arcos-López |first1=Trinidad |title=  Spectroscopic and Theoretical Study of Cu<sup>I</sup> Binding to His111 in the Human Prion Protein Fragment 106–115|journal=  Inorganic Chemistry|date=1 March 2016 |volume=55 |issue= 6|pages=2909–22 |doi=10.1021/acs.inorgchem.5b02794 |pmid=26930130 |pmc=4804749 |hdl=11336/52826 |hdl-access=free }}</ref> Moreover, studies have suggested that, [[in vivo]], due to PrP<sup>C</sup>'s low [[Binding selectivity|selectivity]] to metallic substrates, the protein's anti oxidative function is impaired when in contact with metals other than copper.<ref>{{cite journal |last1=Wong |first1=Boon-Seng |title=A Yin-Yang role for metals in prion disease |journal=Panminerva Medica (2001) |date=December 2001 |volume=43 |issue=4 |pages=283–7 |pmid=11677424 }}</ref> PrP<sup>C</sup> is readily [[Digestion|digested]] by [[proteinase K]] and can be [[Exocytosis|liberated]] from the cell surface by the enzyme [[phospholipase C|phosphoinositide phospholipase C]] (PI-PLC), which [[Bond cleavage|cleaves]] the [[glycophosphatidylinositol]] (GPI) glycolipid anchor.<ref name="weissmann">{{cite journal | vauthors = Weissmann C | title = The state of the prion | journal = Nature Reviews. Microbiology | volume = 2 | issue = 11 | pages = 861–871 | date = November 2004 | pmid = 15494743 | doi = 10.1038/nrmicro1025 | s2cid = 20992257 }}</ref> PrP plays an important role in [[cell-cell adhesion]] and [[intracellular signaling]] ''in vivo'',<ref>{{cite journal | vauthors = Málaga-Trillo E, Solis GP, Schrock Y, Geiss C, Luncz L, Thomanetz V, Stuermer CA | title = Regulation of embryonic cell adhesion by the prion protein | journal = PLOS Biology | volume = 7 | issue = 3 | page = e55 | date = March 2009 | pmid = 19278297 | pmc = 2653553 | doi = 10.1371/journal.pbio.1000055 | veditors = Weissmann C | doi-access = free }}</ref> and may therefore be involved in cell-cell communication in the brain.<ref>{{cite journal | vauthors =  Liebert A, Bicknell B, Adams R |date=2014 |title=Prion Protein Signaling in the Nervous System—A Review and Perspective |journal=Signal Transduction Insights |language=en |volume=3 |article-number=STI.S12319 |doi=10.4137/STI.S12319 |issn=1178-6434 |doi-access=free }}</ref>

==== PrP<sup>Sc</sup> ====
[[File:Scrapie prions.jpg|alt=Photomicrograph of mouse neurons showing red stained inclusions identified as scrapies prion protein.|thumb|upright=0.8|PrP<sup>Sc</sup> (stained in red) revealed in a photomicrograph of scrapie-infected mouse neuronal cells.]]
The infectious [[isoform]] of PrP, known as PrP<sup>Sc</sup>, or simply the prion, is able to convert normal PrP<sup>C</sup> proteins into the infectious isoform by changing their [[Protein structure|conformation]], or shape; this, in turn, alters the way the proteins [[Protein–protein interaction|interact]]. PrP<sup>Sc</sup> always causes prion disease. PrP<sup>Sc</sup> has a higher proportion of [[beta sheet|β-sheet]] structure in place of the normal [[alpha helix|α-helix]] structure.<ref>{{cite journal | vauthors = Caughey BW, Dong A, Bhat KS, Ernst D, Hayes SF, Caughey WS | title = Secondary structure analysis of the scrapie-associated protein PrP 27-30 in water by infrared spectroscopy | journal = Biochemistry | volume = 30 | issue = 31 | pages = 7672–80 | date = August 1991 | pmid = 1678278 | doi = 10.1021/bi00245a003 }}</ref><ref>{{cite journal | vauthors = Safar J, Roller PP, Gajdusek DC, Gibbs CJ | title = Conformational transitions, dissociation, and unfolding of scrapie amyloid (prion) protein | journal = The Journal of Biological Chemistry | volume = 268 | issue = 27 | pages = 20276–84 | date = September 1993 | pmid = 8104185 | doi = 10.1016/s0021-9258(20)80725-x | doi-access = free }}</ref><ref>{{cite journal | vauthors = Pan KM, Baldwin M, Nguyen J, Gasset M, Serban A, Groth D, Mehlhorn I, Huang Z, Fletterick RJ, Cohen FE | title = Conversion of alpha-helices into beta-sheets features in the formation of the scrapie prion proteins | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 90 | issue = 23 | pages = 10962–6 | date = December 1993 | pmid = 7902575 | pmc = 47901 | doi = 10.1073/pnas.90.23.10962 | doi-access = free | bibcode = 1993PNAS...9010962P }}</ref> Several highly infectious, brain-derived PrP<sup>Sc</sup> structures have been discovered by [[cryo-electron microscopy]].<ref name=Kraus21>{{cite journal | vauthors = Kraus A, Hoyt F, Schwartz CL, Hansen B, Artikis E, Hughson AG, Raymond GJ, Race B, Baron GS, Caughey B | title = High-resolution structure and strain comparison of infectious mammalian prions | journal = Molecular Cell | volume = 81 | issue = 21 | pages = 4540–51 | date = November 2021 | pmid = 34433091 | doi = 10.1016/j.molcel.2021.08.011 }}</ref><ref>{{cite journal | vauthors = Hoyt F, Standke HG, Artikis E, Schwartz CL, Hansen B, Li K, Hughson AG, Manca M, Thomas OR, Raymond GJ, Race B, Baron GS, Caughey B, Kraus A | title = Cryo-EM structure of anchorless RML prion reveals variations in shared motifs between distinct strains | journal = Nature Communications | volume = 13 | issue = 1 | article-number = 4005 | date = July 2022 | pmid = 35831291 | pmc = 9279418 | doi = 10.1038/s41467-022-30458-6 | bibcode = 2022NatCo..13.4005H }}</ref><ref>{{cite journal | vauthors = Manka SW, Zhang W, Wenborn A, Betts J, Joiner S, Saibil HR, Collinge J, Wadsworth JD | title = 2.7 Å cryo-EM structure of ex vivo RML prion fibrils | journal = Nature Communications | volume = 13 | issue = 1 | article-number = 4004 | date = July 2022 | pmid = 35831275 | pmc = 9279362 | doi = 10.1038/s41467-022-30457-7 | bibcode = 2022NatCo..13.4004M }}</ref> Another brain-derived [[fibril]] structure isolated from humans with [[Gerstmann–Sträussler–Scheinker syndrome|Gerstmann-Straussler-Schienker syndrome]] has also been determined.<ref>{{cite journal | vauthors = Hallinan GI, Ozcan KA, Hoq MR, Cracco L, Vago FS, Bharath SR, Li D, Jacobsen M, Doud EH, Mosley AL, Fernandez A, Garringer HJ, Jiang W, Ghetti B, Vidal R | title = Cryo-EM structures of prion protein filaments from Gerstmann-Sträussler-Scheinker disease | journal = Acta Neuropathologica | volume = 144 | issue = 3 | pages = 509–520 | date = September 2022 | pmid = 35819518 | pmc = 9381446 | doi = 10.1007/s00401-022-02461-0 }}</ref> All of the structures described in high resolution so far are [[amyloid]] fibers in which individual PrP molecules are stacked via intermolecular beta sheets. However, 2-D [[Crystalline form|crystalline arrays]] have also been reported at lower resolution in ''ex vivo'' preparations of prions.<ref>{{cite journal | vauthors = Wille H, Michelitsch MD, Guenebaut V, Supattapone S, Serban A, Cohen FE, Agard DA, Prusiner SB | title = Structural studies of the scrapie prion protein by electron crystallography | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 99 | issue = 6 | pages = 3563–8 | date = March 2002 | pmid = 11891310 | pmc = 122563 | doi = 10.1073/pnas.052703499 | doi-access = free | bibcode = 2002PNAS...99.3563W }}</ref> In the prion amyloids, the [[glycolipid]] anchors and [[asparagine]]-linked glycans, when present, project outward from the lateral surfaces of the fiber cores. Often PrP<sup>Sc</sup> is bound to cellular membranes, presumably via its array of glycolipid anchors, however, sometimes the fibers are dissociated from membranes and accumulate outside of cells in the form of plaques. The end of each fiber acts as a template onto which free protein molecules may attach, allowing the fiber to grow. This growth process requires complete refolding of PrP<sup>C</sup>.<ref name=Kraus21/> Different prion strains have distinct templates, or conformations, even when composed of PrP molecules of the same [[amino acid sequence]], as occurs in a particular host [[genotype]].<ref>{{cite journal | vauthors = Bessen RA, Kocisko DA, Raymond GJ, Nandan S, Lansbury PT, Caughey B | title = Non-genetic propagation of strain-specific properties of scrapie prion protein | journal = Nature | volume = 375 | issue = 6533 | pages = 698–700 | date = June 1995 | pmid = 7791905 | doi = 10.1038/375698a0 | s2cid = 4355092 | bibcode = 1995Natur.375..698B }}</ref><ref>{{cite journal | vauthors = Telling GC, Parchi P, DeArmond SJ, Cortelli P, Montagna P, Gabizon R, Mastrianni J, Lugaresi E, Gambetti P, Prusiner SB | title = Evidence for the conformation of the pathologic isoform of the prion protein enciphering and propagating prion diversity | journal = Science | volume = 274 | issue = 5295 | pages = 2079–82 | date = December 1996 | pmid = 8953038 | doi = 10.1126/science.274.5295.2079 | bibcode = 1996Sci...274.2079T }}</ref><ref>{{cite journal | vauthors = Safar J, Wille H, Itri V, Groth D, Serban H, Torchia M, Cohen FE, Prusiner SB | title = Eight prion strains have PrP(Sc) molecules with different conformations | journal = Nature Medicine | volume = 4 | issue = 10 | pages = 1157–65 | date = October 1998 | pmid = 9771749 | doi = 10.1038/2654 | bibcode = 1998NatMe...4.1157S | s2cid = 6031488 }}</ref><ref>{{cite journal | vauthors = Hoyt F, Alam P, Artikis E, Schwartz CL, Hughson AG, Race B, Baune C, Raymond GJ, Baron GS, Kraus A, Caughey B | title = Cryo-EM of prion strains from the same genotype of host identifies conformational determinants | journal = PLOS Pathogens | volume = 18 | issue = 11 | article-number = e1010947 | date = November 2022 | pmid = 36342968 | pmc = 9671466 | doi = 10.1371/journal.ppat.1010947 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Manka SW, Wenborn A, Betts J, Joiner S, Saibil HR, Collinge J, Wadsworth JD | title = A structural basis for prion strain diversity | journal = Nature Chemical Biology | volume = 19 | issue = 5 | pages = 607–613 | date = May 2023 | pmid = 36646960 | pmc = 10154210 | doi = 10.1038/s41589-022-01229-7 }}</ref> Under most circumstances, only PrP molecules with an identical amino acid sequence to the infectious PrP<sup>Sc</sup> are incorporated into the growing fiber.<ref name=Krull /> However, [[cross-species transmission]] also happens rarely.<ref name="pmid26809254">{{cite journal | vauthors = Kurt TD, Sigurdson CJ | title = Cross-species transmission of CWD prions | journal = Prion | volume = 10 | issue = 1 | pages = 83–91 | date = 2016 | pmid = 26809254 | pmc = 4981193 | doi = 10.1080/19336896.2015.1118603 }}</ref>

==== PrP<sup>res</sup> ====
Protease-resistant PrP<sup>Sc</sup>-like protein (PrP<sup>res</sup>) is the name given to any isoform of PrP<sup>C</sup> that is structurally altered and converted into a misfolded [[proteinase K]]-resistant form.<ref>{{cite journal | vauthors = Riesner D | title = Biochemistry and structure of PrP(C) and PrP(Sc) | journal = British Medical Bulletin | volume = 66 | issue = 1 | pages = 21–33 | date = June 2003 | pmid = 14522846 | doi = 10.1093/bmb/66.1.21 | doi-access = free }}</ref> To model conversion of PrP<sup>C</sup> to PrP<sup>Sc</sup> ''in vitro'', Kocisko ''et al''. showed that PrP<sup>Sc</sup> could cause PrP<sup>C</sup> to convert to PrP<sup>res</sup> under cell-free conditions. However, the authors state that their results do not rule out the involvement of other non-PrP constituents such as nucleic acids.<ref name="pmid7913989">{{cite journal | vauthors = Kocisko DA, Come JH, Priola SA, Chesebro B, Raymond GJ, Lansbury PT, Caughey B | title = Cell-free formation of protease-resistant prion protein | journal = Nature | volume = 370 | issue = 6489 | pages = 471–4 | date = August 1994 | pmid = 7913989 | doi = 10.1038/370471a0 | bibcode = 1994Natur.370..471K | hdl-access = free | s2cid = 4337709 | hdl = 1721.1/42578 }}</ref> Soto ''et al''. demonstrated sustained amplification of PrP<sup>res</sup> (sample sourced from scrapie-infected brain homogenate) and prion infectivity by a procedure involving [[Protein misfolding cyclic amplification|cyclic amplification of protein misfolding]].<ref name="pmid11459061">{{cite journal | vauthors = Saborio GP, Permanne B, Soto C | title = Sensitive detection of pathological prion protein by cyclic amplification of protein misfolding | journal = Nature | volume = 411 | issue = 6839 | pages = 810–3 | date = June 2001 | pmid = 11459061 | doi = 10.1038/35081095 | bibcode = 2001Natur.411..810S | s2cid = 4317585 }}</ref> The term "PrP<sup>res</sup>" may refer either to protease-resistant forms of PrP<sup>Sc</sup>, which is isolated from infectious tissue and associated with the transmissible spongiform encephalopathy agent, or to other protease-resistant forms of PrP that, for example, might be generated ''in vitro''.<ref name="pmid15297610">{{cite journal | vauthors = Bieschke J, Weber P, Sarafoff N, Beekes M, Giese A, Kretzschmar H | title = Autocatalytic self-propagation of misfolded prion protein | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 101 | issue = 33 | pages = 12207–11 | date = August 2004 | pmid = 15297610 | pmc = 514458 | doi = 10.1073/pnas.0404650101 | bibcode = 2004PNAS..10112207B | doi-access = free }}</ref> Accordingly, unlike PrP<sup>Sc</sup>, PrP<sup>res</sup> may not necessarily be infectious.

[[File:Prion structure membrane bound fibril.jpg|thumb|Models of normal (PrP<sup>C</sup>) and infectious (PrP<sup>Sc</sup>) forms of prion protein on a membrane: polypeptide (turquoise); glycans (red); glycolipid anchors (blue). The core structures are based on NMR spectroscopy (PrP<sup>C</sup>) and cryo-electron microscopy (PrP<sup>Sc</sup>).]]

=== Normal function of PrP ===
The physiological function of the prion protein remains poorly understood. While data from in vitro experiments suggest many dissimilar roles, studies on PrP [[knockout mouse|knockout mice]] have provided only limited information because these animals exhibit only minor abnormalities. Research in mice has found that the cleavage of PrP in peripheral nerves causes the activation of [[myelin]] repair in [[Schwann cells]], and that the lack of PrP proteins causes demyelination in those cells.<ref>{{cite journal | title = Healthy prions protect nerves | journal = Nature | vauthors = Abbott A | s2cid = 84980140 | doi = 10.1038/news.2010.29 | date=2010-01-24 }}</ref>

==== PrP and regulated cell death ====
MAVS, RIP1, and RIP3 are prion-like proteins found in other parts of the body. They also polymerise into filamentous amyloid fibers that initiate regulated cell death in the case of a viral infection to prevent the spread of [[Virus#Etymology|virions]] to other, surrounding cells.<ref>{{cite journal | vauthors = Nailwal H, Chan FK | title = Necroptosis in anti-viral inflammation | journal = Cell Death and Differentiation | volume = 26 | issue = 1 | pages = 4–13 | date = January 2019 | pmid = 30050058 | pmc = 6294789 | doi = 10.1038/s41418-018-0172-x }}</ref> There is evidence that PrP and pathogenic PrP<sup>Sc</sup> contribute to [[ferroptosis]] sensitivity, a condition that is enhanced by RAC3 expression.<ref name="peng">{{Cite journal |last1=Peng |first1=Hao |last2=Pfeiffer |first2=Susanne |last3=Varynskyi |first3=Borys |last4=Qiu |first4=Marina |last5=Srinark |first5=Chanikarn |last6=Jin |first6=Xiang |last7=Zhang |first7=Xin |last8=Williams |first8=Katie |last9=Groveman |first9=Bradley R. |last10=Foliaki |first10=Simote T. |last11=Race |first11=Brent |last12=Thomas |first12=Tina |last13=Chen |first13=Chengxuan |last14=Müller |first14=Constanze |last15=Kovács |first15=Krisztina |date=2025-06-25 |title=Prion-induced ferroptosis is facilitated by RAC3 |journal=Nature Communications |language=en |volume=16 |issue=1 |pages=5385 |doi=10.1038/s41467-025-60793-3 |issn=2041-1723 |pmc=12198409 |pmid=40562790 |bibcode=2025NatCo..16.5385P }}</ref>

==== PrP and long-term memory ====
A review of evidence in 2005 suggested that PrP may have a normal function in the maintenance of [[long-term memory]].<ref>{{cite journal | vauthors = Shorter J, Lindquist S | title = Prions as adaptive conduits of memory and inheritance | journal = Nature Reviews. Genetics | volume = 6 | issue = 6 | pages = 435–450 | date = June 2005 | pmid = 15931169 | doi = 10.1038/nrg1616 | s2cid = 5575951 }}</ref> As well, a 2004 study found that mice lacking genes for normal cellular PrP protein show altered [[hippocampus|hippocampal]] [[long-term potentiation]].<ref>{{cite journal | vauthors = Maglio LE, Perez MF, Martins VR, Brentani RR, Ramirez OA | title = Hippocampal synaptic plasticity in mice devoid of cellular prion protein | journal = Brain Research. Molecular Brain Research | volume = 131 | issue = 1–2 | pages = 58–64 | date = November 2004 | pmid = 15530652 | doi = 10.1016/j.molbrainres.2004.08.004 }}</ref><ref>{{cite journal | vauthors = Caiati MD, Safiulina VF, Fattorini G, Sivakumaran S, Legname G, Cherubini E | title = PrPC controls via protein kinase A the direction of synaptic plasticity in the immature hippocampus | journal = The Journal of Neuroscience | volume = 33 | issue = 7 | pages = 2973–83 | date = February 2013 | pmid = 23407955 | pmc = 6619229 | doi = 10.1523/JNEUROSCI.4149-12.2013 }}</ref> A recent study that also suggests why this might be the case, found that neuronal protein [[CPEB]] has a similar genetic sequence to yeast prion proteins. The prion-like formation of CPEB is essential for maintaining long-term synaptic changes associated with long-term memory formation.<ref>{{cite journal | vauthors = Sudhakaran IP, Ramaswami M | title = Long-term memory consolidation: The role of RNA-binding proteins with prion-like domains | journal = RNA Biology | volume = 14 | issue = 5 | pages = 568–586 | date = May 2017 | pmid = 27726526 | pmc = 5449092 | doi = 10.1080/15476286.2016.1244588 }}</ref>

==== PrP and stem cell renewal ====
A 2006 article from the Whitehead Institute for Biomedical Research indicates that PrP expression on stem cells is necessary for an organism's self-renewal of [[bone marrow]]. The study showed that all long-term [[hematopoietic stem cell]]s express PrP on their cell membrane and that hematopoietic tissues with PrP-null stem cells exhibit increased sensitivity to cell depletion.<ref>{{cite journal | vauthors = Zhang CC, Steele AD, Lindquist S, Lodish HF | title = Prion protein is expressed on long-term repopulating hematopoietic stem cells and is important for their self-renewal | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 103 | issue = 7 | pages = 2184–9 | date = February 2006 | pmid = 16467153 | pmc = 1413720 | doi = 10.1073/pnas.0510577103 | doi-access = free | bibcode = 2006PNAS..103.2184Z }}</ref>

==== PrP and innate immunity ====
There is some evidence that PrP may play a role in [[innate immunity]], as the expression of [[PRNP]], the PrP gene, is upregulated in many viral infections and PrP has antiviral properties against many viruses, including [[HIV]].<ref>{{cite journal | vauthors = Lathe R, Darlix JL | title = Prion Protein PRNP: A New Player in Innate Immunity? The Aβ Connection | journal = Journal of Alzheimer's Disease Reports | volume = 1 | issue = 1 | pages = 263–275 | date = December 2017 | pmid = 30480243 | pmc = 6159716 | doi = 10.3233/ADR-170037 }}</ref>

== Replication ==
[[File:Prion propagation.svg|thumb|Heterodimer model of prion propagation]]
[[File:Prion Replication.png|thumb|right|Fibril model of prion propagation]]

The first hypothesis that tried to explain how prions replicate in a protein-only manner was the [[Protein dimer|heterodimer]] model.<ref>{{cite journal | vauthors = Cohen FE, Pan KM, Huang Z, Baldwin M, Fletterick RJ, Prusiner SB | title = Structural clues to prion replication | journal = Science | volume = 264 | issue = 5158 | pages = 530–1 | date = April 1994 | pmid = 7909169 | doi = 10.1126/science.7909169 | bibcode = 1994Sci...264..530C }}</ref> This model assumed that a single PrP<sup>Sc</sup> molecule binds to a single PrP<sup>C</sup> molecule and [[enzyme|catalyzes]] its conversion into PrP<sup>Sc</sup>. The two PrP<sup>Sc</sup> molecules then come apart and can go on to convert more PrP<sup>C</sup>. However, a model of prion replication must explain both how prions propagate, and why their spontaneous appearance is so rare. [[Manfred Eigen]] showed that the heterodimer model requires PrP<sup>Sc</sup> to be an extraordinarily effective catalyst, increasing the rate of the conversion reaction by a factor of around 10<sup>15</sup>.<ref name="Eigen96">{{cite journal | vauthors = Eigen M | title = Prionics or the kinetic basis of prion diseases | journal = Biophysical Chemistry | volume = 63 | issue = 1 | pages = A1-18 | date = December 1996 | pmid = 8981746 | doi = 10.1016/S0301-4622(96)02250-8 }}</ref> This problem does not arise if PrP<sup>Sc</sup> exists only in aggregated forms such as [[amyloid]], where [[cooperativity]] may act as a barrier to spontaneous conversion. What is more, despite considerable effort, infectious monomeric PrP<sup>Sc</sup> has never been isolated.<ref>{{cite journal | vauthors = Vázquez-Fernández E, Young HS, Requena JR, Wille H | title = The Structure of Mammalian Prions and Their Aggregates | journal = International Review of Cell and Molecular Biology | volume = 329 | pages = 277–301 | date = 2017 | pmid = 28109330 | doi = 10.1016/bs.ircmb.2016.08.013 | isbn = 978-0-12-812251-8 }}</ref>

An alternative model assumes that PrP<sup>Sc</sup> exists only as [[fibril]]s, and that fibril ends bind PrP<sup>C</sup> and convert it into PrP<sup>Sc</sup>. If this were all, then the quantity of prions would increase [[linear function|linearly]], forming ever longer fibrils. But [[exponential growth]] of both PrP<sup>Sc</sup> and the [[Median lethal dose|quantity of infectious particles]] is observed during prion disease.<ref>{{cite journal | vauthors = Bolton DC, Rudelli RD, Currie JR, Bendheim PE | title = Copurification of Sp33-37 and scrapie agent from hamster brain prior to detectable histopathology and clinical disease | journal = The Journal of General Virology | volume = 72 | issue = 12 | pages = 2905–13 | date = December 1991 | pmid = 1684986 | doi = 10.1099/0022-1317-72-12-2905 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Jendroska K, Heinzel FP, Torchia M, Stowring L, Kretzschmar HA, Kon A, Stern A, Prusiner SB, DeArmond SJ | title = Proteinase-resistant prion protein accumulation in Syrian hamster brain correlates with regional pathology and scrapie infectivity | journal = Neurology | volume = 41 | issue = 9 | pages = 1482–90 | date = September 1991 | pmid = 1679911 | doi = 10.1212/WNL.41.9.1482 | s2cid = 13098083 }}</ref><ref>{{cite journal | vauthors = Beekes M, Baldauf E, Diringer H | title = Sequential appearance and accumulation of pathognomonic markers in the central nervous system of hamsters orally infected with scrapie | journal = The Journal of General Virology | volume = 77 ( Pt 8) | issue = 8 | pages = 1925–34 | date = August 1996 | pmid = 8760444 | doi = 10.1099/0022-1317-77-8-1925 | doi-access = free }}</ref> This can be explained by taking into account fibril breakage.<ref>{{cite journal | vauthors = Bamborough P, Wille H, Telling GC, Yehiely F, Prusiner SB, Cohen FE | title = Prion protein structure and scrapie replication: theoretical, spectroscopic, and genetic investigations | journal = Cold Spring Harbor Symposia on Quantitative Biology | volume = 61 | pages = 495–509 | year = 1996 | pmid = 9246476 | doi = 10.1101/SQB.1996.061.01.050 | doi-broken-date = July 1, 2025 }}</ref> A mathematical solution for the exponential growth rate resulting from the combination of fibril growth and fibril breakage has been found.<ref name="Masel 99" /> The exponential growth rate depends largely on the [[square root]] of the PrP<sup>C</sup> concentration.<ref name="Masel 99" /> The [[incubation period]] is determined by the exponential growth rate, and [[in vivo]] data on prion diseases in [[transgenic mice]] match this prediction.<ref name="Masel 99" /> The same square root dependence is also seen [[in vitro]] in experiments with a variety of different [[amyloid|amyloid proteins]].<ref>{{cite journal | vauthors = Knowles TP, Waudby CA, Devlin GL, Cohen SI, Aguzzi A, Vendruscolo M, Terentjev EM, Welland ME, Dobson CM | title = An analytical solution to the kinetics of breakable filament assembly | journal = Science | volume = 326 | issue = 5959 | pages = 1533–7 | date = December 2009 | pmid = 20007899 | doi = 10.1126/science.1178250 | s2cid = 6267152 | bibcode = 2009Sci...326.1533K }}</ref>

The mechanism of prion replication has implications for designing drugs. Since the incubation period of prion diseases is so long, an effective drug does not need to eliminate all prions, but simply needs to slow down the rate of exponential growth. Models predict that the most effective way to achieve this, using a drug with the lowest possible dose, is to find a drug that binds to fibril ends and blocks them from growing any further.<ref>{{cite journal | vauthors = Masel J, Jansen VA | title = Designing drugs to stop the formation of prion aggregates and other amyloids | journal = Biophysical Chemistry | volume = 88 | issue = 1–3 | pages = 47–59 | date = December 2000 | pmid = 11152275 | doi = 10.1016/S0301-4622(00)00197-6 | doi-access = free }}</ref>

Researchers at Dartmouth College discovered that endogenous host cofactor molecules such as the phospholipid molecule (e.g. phosphatidylethanolamine) and [[polyanions]] (e.g. single stranded RNA molecules) are necessary to form PrP<sup>Sc</sup> molecules with high levels of specific infectivity ''in vitro'', whereas protein-only PrP<sup>Sc</sup> molecules appear to lack significant levels of biological infectivity.<ref name="Formation of native prions from min">{{cite journal | vauthors = Deleault NR, Harris BT, Rees JR, Supattapone S | title = Formation of native prions from minimal components in vitro | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 104 | issue = 23 | pages = 9741–6 | date = June 2007 | pmid = 17535913 | pmc = 1887554 | doi = 10.1073/pnas.0702662104 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Deleault NR, Walsh DJ, Piro JR, Wang F, Wang X, Ma J, Rees JR, Supattapone S | title = Cofactor molecules maintain infectious conformation and restrict strain properties in purified prions | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 109 | issue = 28 | pages = E1938–E1946 | date = July 2012 | pmid = 22711839 | pmc = 3396481 | doi = 10.1073/pnas.1206999109 | doi-access = free }}</ref>

== Transmissible spongiform encephalopathies ==
{{Main|Transmissible spongiform encephalopathy}}
{| class = "wikitable floatright" style = "font-size:90%"
|+Diseases caused by prions
|-
! width="130" |Affected animal(s)
! width="250" |Disease
|-
|[[Domestic sheep|Sheep]], [[goat]]
|[[Scrapie]]<ref name="ictvdb-prions">{{cite web | url=https://www.ncbi.nlm.nih.gov/ICTVdb/Ictv/fs_prion.htm | title=90. Prions | work=ICTVdB Index of Viruses | publisher=U.S. National Institutes of Health website | date=2002-02-14 | access-date=2010-02-28 | archive-date=2009-08-27 | archive-url=https://web.archive.org/web/20090827131816/http://www.ncbi.nlm.nih.gov/ICTVdb/Ictv/fs_prion.htm | url-status=dead }}</ref>
|-
|[[Cattle]]
|[[Bovine spongiform encephalopathy]]<ref name="ictvdb-prions" />
|-
|[[Camel]]<ref>{{cite journal | vauthors = Babelhadj B, Di Bari MA, Pirisinu L, Chiappini B, Gaouar SB, Riccardi G, Marcon S, Agrimi U, Nonno R, Vaccari G | title = Prion Disease in Dromedary Camels, Algeria | journal = Emerging Infectious Diseases | volume = 24 | issue = 6 | pages = 1029–36 | date = June 2018 | pmid = 29652245 | pmc = 6004840 | doi = 10.3201/eid2406.172007 }}</ref>
|[[Camel spongiform encephalopathy]]
|-
|[[Mink]]<ref name="ictvdb-prions" />
|[[Transmissible mink encephalopathy]]
|-
|[[White-tailed deer]], [[elk]], [[mule deer]], [[moose]]<ref name="ictvdb-prions" />
|[[Chronic wasting disease]]
|-
|[[Cat]]<ref name="ictvdb-prions" />
|[[Feline spongiform encephalopathy]]
|-
|[[Nyala]], [[oryx]], [[greater kudu]]<ref name="ictvdb-prions" />
|[[Exotic ungulate encephalopathy]]
|-
|[[Ostrich]]<ref name="hussein2004">{{cite journal |vauthors=Hussein MF, Al-Mufarrej SI |year=2004 |url=https://apps.kfu.edu.sa/sjournal/ara/pdffiles/b526.pdf |title=Prion Diseases: A Review; II. Prion Diseases in Man and Animals |journal=Scientific Journal of King Faisal University (Basic and Applied Sciences) |issue=2 |page=139 |access-date=April 9, 2016 |volume=5 |archive-date=April 21, 2016 |archive-url=https://web.archive.org/web/20160421204236/https://apps.kfu.edu.sa/sjournal/ara/pdffiles/b526.pdf |url-status=live }}</ref>
|Spongiform encephalopathy<br />(unknown whether transmissible)
|-
| rowspan="9" |Human
|[[Creutzfeldt–Jakob disease]]<ref name="ictvdb-prions" />
|-
|[[Iatrogenesis|Iatrogenic]] Creutzfeldt–Jakob disease
|-
|[[Variant Creutzfeldt–Jakob disease]]
|-
|Sporadic Creutzfeldt–Jakob disease
|-
|[[Gerstmann–Sträussler–Scheinker syndrome]]<ref name="ictvdb-prions" />
|-
|[[Fatal insomnia]]<ref>{{cite journal | vauthors = Mastrianni JA, Nixon R, Layzer R, Telling GC, Han D, DeArmond SJ, Prusiner SB | title = Prion protein conformation in a patient with sporadic fatal insomnia | journal = The New England Journal of Medicine | volume = 340 | issue = 21 | pages = 1630–8 | date = May 1999 | pmid = 10341275 | doi = 10.1056/NEJM199905273402104 | doi-access = free }}<br />Lay summary: {{cite web |title=BSE proteins may cause fatal insomnia |url=http://news.bbc.co.uk/2/hi/health/355297.stm |date=May 28, 1999|website=BBC News}}</ref>
|-
|[[Kuru (disease)|Kuru]]<ref name="ictvdb-prions" />
|-
| <!---Familiar spongiform encephalopathy associated with a novel prion protein gene mutation--->[[Familial spongiform encephalopathy]]<ref>{{cite journal | vauthors = Nitrini R, Rosemberg S, Passos-Bueno MR, da Silva LS, Iughetti P, Papadopoulos M, Carrilho PM, Caramelli P, Albrecht S, Zatz M, LeBlanc A | title = Familial spongiform encephalopathy associated with a novel prion protein gene mutation | journal = Annals of Neurology | volume = 42 | issue = 2 | pages = 138–146 | date = August 1997 | pmid = 9266722 | doi = 10.1002/ana.410420203 | s2cid = 22600579 }}</ref>
|-
|[[Variably protease-sensitive prionopathy]]
|-
|}

Prions cause neurodegenerative disease by aggregating extracellularly within the [[central nervous system]] to form plaques known as [[amyloids]], which disrupt the normal [[tissue (biology)|tissue]] structure. This disruption is characterized by "holes" in the tissue with resultant spongy architecture due to the [[vacuole]] formation in the neurons.<ref name="robspath">{{cite book | veditors = Robbins SL, Cotran RS, Kumar V, Collins T | title = Robbins pathologic basis of disease | publisher = Saunders | location = Philadelphia | year =1999 | isbn = 0-7216-7335-X }}</ref> Other histological changes include [[astrogliosis]] and the absence of an [[inflammation|inflammatory reaction]].<ref name="belay">{{cite journal | vauthors = Belay ED | title = Transmissible spongiform encephalopathies in humans | journal = Annual Review of Microbiology | volume = 53 | pages = 283–314 | year = 1999 | pmid = 10547693 | doi = 10.1146/annurev.micro.53.1.283 | s2cid = 18648029 }}</ref> While the [[incubation period]] for human prion diseases is relatively long (5 to 20 years or more), once symptoms appear the disease progresses rapidly, leading to brain damage and death.<ref name="cdc">{{cite web|url=https://www.cdc.gov/ncidod/dvrd/prions/|title=Prion Diseases|date=2006-01-26|access-date=2010-02-28|publisher=US Centers for Disease Control|archive-url=https://web.archive.org/web/20100304135757/http://www.cdc.gov/ncidod/dvrd/prions/|archive-date=2010-03-04|url-status=dead}}</ref><ref>{{cite journal | vauthors=Collinge J, Whitfield J, McKintosh E, Frosh A, Mead S, Hill AF, Brandner S, Thomas D, Alpers MP | date=2008 | title= A clinical study of kuru patients with long incubation periods at the end of the epidemic in Papua New Guinea | journal=Philosophical Transactions of the Royal Society of London B: Biological Sciences | volume=363 | issue=1510 | pages=3725–3739| doi=10.1098/rstb.2008.0068 | pmc=2581654 | pmid=18849289}}</ref> Neurodegenerative symptoms can include [[convulsion]]s, [[dementia]], [[ataxia]] (balance and coordination dysfunction), and behavioural or personality changes.<ref>{{cite journal | vauthors = Imran M, Mahmood S | title = An overview of human prion diseases | journal = Virology Journal | volume = 8 | issue = 1 | article-number = 559 | date = December 2011 | pmid = 22196171 | pmc = 3296552 | doi = 10.1186/1743-422X-8-559 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Mastrianni JA | title = The genetics of prion diseases | journal = Genetics in Medicine | volume = 12 | issue = 4 | pages = 187–195 | date = April 2010 | pmid = 20216075 | doi = 10.1097/GIM.0b013e3181cd7374 | doi-access = free }}</ref>

Many different mammalian species can be affected by prion diseases, as the prion protein (PrP) is very similar in all mammals.<ref>{{cite journal | vauthors = Collinge J | title = Prion diseases of humans and animals: their causes and molecular basis | journal = Annual Review of Neuroscience | volume = 24 | pages = 519–550 | year = 2001 | pmid = 11283320 | doi = 10.1146/annurev.neuro.24.1.519 | url = http://pdfs.semanticscholar.org/650f/8f4c880880d357e5dd82236ba611065e21cc.pdf | url-status = dead | s2cid = 18915904 | archive-url = https://web.archive.org/web/20190225162649/http://pdfs.semanticscholar.org/650f/8f4c880880d357e5dd82236ba611065e21cc.pdf | archive-date = 2019-02-25 }}</ref> Due to small differences in PrP between different species it is unusual for a prion disease to transmit from one species to another. The human prion disease variant Creutzfeldt–Jakob disease, however, is thought to be caused by a prion that typically infects cattle (causing [[bovine spongiform encephalopathy]]) and that is transmitted through infected meat.<ref name="ironside">{{cite journal | vauthors = Ironside JW | title = Variant Creutzfeldt-Jakob disease: risk of transmission by blood transfusion and blood therapies | journal = Haemophilia | volume = 12 | issue = Suppl 1 | pages = 8–15, discussion 26–28 | date = March 2006 | pmid = 16445812 | doi = 10.1111/j.1365-2516.2006.01195.x | doi-access = free }}</ref>

All known prion diseases are untreatable and fatal.<ref name=":0">{{cite journal | vauthors = Prusiner SB | title = Prions | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 95 | issue = 23 | pages = 13363–83 | date = November 1998 | pmid = 9811807 | pmc = 33918 | doi = 10.1073/pnas.95.23.13363 | doi-access = free | bibcode = 1998PNAS...9513363P }}</ref><ref name="gilch">{{cite journal | vauthors = Gilch S, Winklhofer KF, Groschup MH, Nunziante M, Lucassen R, Spielhaupter C, Muranyi W, Riesner D, Tatzelt J, Schätzl HM | title = Intracellular re-routing of prion protein prevents propagation of PrP(Sc) and delays onset of prion disease | journal = The EMBO Journal | volume = 20 | issue = 15 | pages = 3957–66 | date = August 2001 | pmid = 11483499 | pmc = 149175 | doi = 10.1093/emboj/20.15.3957 }}</ref><ref>{{cite journal | vauthors = Agarwal A, Mukhopadhyay S | title = Prion Protein Biology Through the Lens of Liquid-Liquid Phase Separation | journal = Journal of Molecular Biology | volume = 434 | issue = 1 | article-number = 167368 | date = January 2022 | pmid = 34808226 | doi = 10.1016/j.jmb.2021.167368 }}</ref>

Until 2015 all known mammalian prion diseases were considered to be caused by the prion protein, [[PRNP|PrP]]. After 2015 this remains true for diseases in the category of "transmissible spongiform encephalopathy" (TSE), which is transmissible and causes a specific sponge-like appearance of infected brain tissue. The endogenous, properly folded form of the prion protein is denoted PrP<sup>C</sup> (for '''''C'''ommon'' or '''''C'''ellular''), whereas the disease-linked, misfolded form is denoted PrP<sup>Sc</sup> (for '''''Sc'''rapie''), after one of the diseases first linked to prions and [[neurodegeneration]].<ref name=Krull /><ref name="pmid19242475"/> The precise structure of the prion is not known, though they can be formed spontaneously by combining PrP<sup>C</sup>, homopolymeric polyadenylic acid, and lipids in a [[protein misfolding cyclic amplification]] (PMCA) reaction even in the absence of pre-existing infectious prions.<ref name="Formation of native prions from min"/> This result is further evidence that prion replication does not require genetic information.<ref name="pmid28838669">{{cite journal | vauthors = Moda F | title = Protein Misfolding Cyclic Amplification of Infectious Prions | journal = Progress in Molecular Biology and Translational Science | volume = 150 | pages = 361–374 | date = 2017 | pmid = 28838669 | doi = 10.1016/bs.pmbts.2017.06.016 | isbn = 978-0-12-811226-7 }}</ref>

=== Transmission ===
Prion diseases can arise in three different ways: acquired, familial, or sporadic.<ref>{{cite book | veditors = Groschup MH, Kretzschmar HA | title = Prion Diseases Diagnosis and Pathogeneis | series = Archives of Virology | volume = 16 | location = New York | publisher = Springer | year = 2001 | isbn=978-3-211-83530-2 |doi=10.1007/978-3-7091-6308-5}}</ref> It is often assumed that the disease-related form (PrP<sup>Sc</sup>) directly interacts with the normal form (PrP<sup>C</sup>) to make it rearrange its structure. One idea, the "Protein X" hypothesis, is that an as-yet unidentified cellular protein (Protein X) enables the conversion of PrP<sup>C</sup> to PrP<sup>Sc</sup> by bringing a molecule of each of the two together into a complex.<ref>{{cite journal | vauthors = Telling GC, Scott M, Mastrianni J, Gabizon R, Torchia M, Cohen FE, DeArmond SJ, Prusiner SB | title = Prion propagation in mice expressing human and chimeric PrP transgenes implicates the interaction of cellular PrP with another protein | journal = Cell | volume = 83 | issue = 1 | pages = 79–90 | date = October 1995 | pmid = 7553876 | doi = 10.1016/0092-8674(95)90236-8 | s2cid = 15235574 | doi-access = free }}</ref>

The primary method of prion infection in animals is through ingestion of PrP<sup>Sc</sup>. It is thought that prions may be deposited in the environment through the remains of dead animals and via urine, saliva, and other body fluids. They may then linger in the soil by binding to clay and other minerals.<ref>{{cite journal | vauthors = Johnson CJ, Pedersen JA, Chappell RJ, McKenzie D, Aiken JM | title = Oral transmissibility of prion disease is enhanced by binding to soil particles | journal = PLOS Pathogens | volume = 3 | issue = 7 | page = e93 | date = July 2007 | pmid = 17616973 | pmc = 1904474 | doi = 10.1371/journal.ppat.0030093 | doi-access = free }}</ref>

A [[University of California]] research team has provided evidence that infection can occur from prions in feces.<ref>{{cite journal | vauthors = Tamgüney G, Miller MW, Wolfe LL, Sirochman TM, Glidden DV, Palmer C, Lemus A, DeArmond SJ, Prusiner SB | title = Asymptomatic deer excrete infectious prions in faeces | journal = Nature | volume = 461 | issue = 7263 | pages = 529–532 | date = September 2009 | pmid = 19741608 | pmc = 3186440 | doi = 10.1038/nature08289 | bibcode = 2009Natur.461..529T }}</ref> Since animal excrement is present in many areas surrounding water reservoirs, and manure is used to fertilize many crop fields, this raises the possibility of widespread transmission. Preliminary evidence suggesting that prions might be transmitted through the use of urine-derived [[human menopausal gonadotropin]], administered for the treatment of [[infertility]], was published in 2011.<ref name="pmid21448279">{{cite journal | vauthors = Van Dorsselaer A, Carapito C, Delalande F, Schaeffer-Reiss C, Thierse D, Diemer H, McNair DS, Krewski D, Cashman NR | title = Detection of prion protein in urine-derived injectable fertility products by a targeted proteomic approach | journal = PLOS ONE | volume = 6 | issue = 3 | article-number = e17815 | date = March 2011 | pmid = 21448279 | pmc = 3063168 | doi = 10.1371/journal.pone.0017815 | doi-access = free | bibcode = 2011PLoSO...617815V }}</ref>

==== Genetic susceptibility ====
The majority of human prion diseases are classified as sporadic ([[idiopathic]]) Creutzfeldt–Jakob disease (sCJD). Genetic research has identified an association between susceptibility to sCJD and a polymorphism at codon 129 in the PRNP gene, which encodes the prion protein (PrP). A homozygous methionine/methionine (MM) genotype at this position has been shown to significantly increase the risk of developing sCJD when compared to a heterozygous methionine/valine (MV) genotype. Analysis of multiple studies has shown that individuals with the MM genotype are approximately five times more likely to develop sCJD than those with the MV genotype.<ref>{{cite journal |vauthors=Kim YC, Jeong BH |title=The First Meta-Analysis of the M129V Single-Nucleotide Polymorphism (SNP) of the Prion Protein Gene (PRNP) with Sporadic Creutzfeldt-Jakob Disease |journal=Cells |volume=10 |issue=11 |date=November 2021 |page=3132 |pmid=34831353 |pmc=8618741 |doi=10.3390/cells10113132 |doi-access=free}}</ref>

==== Prions in plants ====
In 2015, researchers at [[The University of Texas Health Science Center at Houston]] found that plants can be a vector for prions. When researchers fed hamsters grass that grew on ground where a deer that died with [[chronic wasting disease]] was buried, the hamsters became ill with CWD. The findings suggest that prions can be taken up by plants that are eaten by herbivores, thus completing the cycle. It is thus possible that there is a progressively accumulating number of prions in the environment.<ref>{{cite news |vauthors=Beecher C |url=http://www.foodsafetynews.com/2015/06/researchers-make-surprising-discovery-about-spread-of-chronic-wasting-disease/ |title=Surprising' Discovery Made About Chronic Wasting Disease |work=[[Food Safety News]] |date=June 1, 2015 |access-date=2016-04-08 |archive-date=2016-04-28 |archive-url=https://web.archive.org/web/20160428055600/http://www.foodsafetynews.com/2015/06/researchers-make-surprising-discovery-about-spread-of-chronic-wasting-disease/ |url-status=live }}</ref><ref>{{cite journal | vauthors = Pritzkow S, Morales R, Moda F, Khan U, Telling GC, Hoover E, Soto C | title = Grass plants bind, retain, uptake, and transport infectious prions | journal = Cell Reports | volume = 11 | issue = 8 | pages = 1168–75 | date = May 2015 | pmid = 25981035 | pmc = 4449294 | doi = 10.1016/j.celrep.2015.04.036 }}</ref>

=== Sterilization ===
Infectious agents possessing [[nucleic acid]]s are dependent upon [[DNA]] or [[RNA]] to direct their continued replication. Prions, however, derive their infectivity from their ability to transform normal PrP to PrP<sup>Sc</sup>, the misshapen, disease-causing conformation. Inactivating prions via sterilization, therefore, requires the [[denaturation (biochemistry)|denaturation]] of the protein to a state in which the molecule is no longer able to induce the abnormal folding of normal PrP. In general, prions are resistant to [[protease]]s, heat, [[ionizing radiation]], and [[formaldehyde]] treatments,<ref>{{cite journal | vauthors = Qin K, O'Donnell M, Zhao RY | title = Doppel: more rival than double to prion | journal = Neuroscience | volume = 141 | issue = 1 | pages = 1–8 | date = August 2006 | pmid = 16781817 | doi = 10.1016/j.neuroscience.2006.04.057 | s2cid = 28822120 }}</ref> although their infectivity can be reduced by such treatments. Effective prion decontamination relies upon protein [[hydrolysis]] or reduction or destruction of [[protein tertiary structure]]. Examples of such sterilization agents include [[sodium hypochlorite]], [[sodium hydroxide]], and strongly acidic [[detergent]]s such as LpH.<ref>{{cite journal | vauthors = Race RE, Raymond GJ | title = Inactivation of transmissible spongiform encephalopathy (prion) agents by environ LpH | journal = Journal of Virology | volume = 78 | issue = 4 | pages = 2164–5 | date = February 2004 | pmid = 14747583 | pmc = 369477 | doi = 10.1128/JVI.78.4.2164-2165.2004 }}</ref>

The [[World Health Organization]] recommends any of the following three procedures for the sterilization of all heat-resistant surgical instruments to ensure that they are not contaminated with prions:
# Immerse in [[Equivalent concentration|1N]]&nbsp;sodium hydroxide and place in a [[Autoclave#Air removal|gravity-displacement autoclave]] at 121&nbsp;°C for 30&nbsp;minutes; clean; rinse in water; and then perform routine sterilization processes.
# Immerse in 1N&nbsp;sodium hypochlorite (20,000&nbsp;parts per million available chlorine) for 1&nbsp;hour; transfer instruments to water; heat in a gravity-displacement autoclave at 121&nbsp;°C for 1&nbsp;hour; clean; and then perform routine sterilization processes.
# Immerse in 1N&nbsp;sodium hydroxide or sodium hypochlorite (20,000&nbsp;parts per million available chlorine) for 1&nbsp;hour; remove and rinse in water, then transfer to an open pan and heat in a gravity-displacement (121&nbsp;°C) or in a porous-load (134&nbsp;°C) autoclave for 1&nbsp;hour; clean; and then perform routine sterilization processes.<ref>{{cite journal | vauthors = Sutton JM, Dickinson J, Walker JT, Raven ND | title = Methods to minimize the risks of Creutzfeldt-Jakob disease transmission by surgical procedures: where to set the standard? | journal = Clinical Infectious Diseases | volume = 43 | issue = 6 | pages = 757–764 | date = September 2006 | pmid = 16912952 | doi = 10.1086/507030 | doi-access = free }}</ref>

Heating at {{convert|134|C}} for 18 minutes in a pressurized steam [[autoclave]] has been found to be somewhat effective in deactivating prions.<ref>{{cite journal | vauthors = Collins SJ, Lawson VA, Masters CL | title = Transmissible spongiform encephalopathies | journal = Lancet | volume = 363 | issue = 9402 | pages = 51–61 | date = January 2004 | pmid = 14723996 | doi = 10.1016/S0140-6736(03)15171-9 | s2cid = 23212525 }}</ref><ref name="pmid10716712">{{cite journal | vauthors = Brown P, Rau EH, Johnson BK, Bacote AE, Gibbs CJ, Gajdusek DC | title = New studies on the heat resistance of hamster-adapted scrapie agent: threshold survival after ashing at 600 degrees C suggests an inorganic template of replication | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 97 | issue = 7 | pages = 3418–21 | date = March 2000 | pmid = 10716712 | pmc = 16254 | doi = 10.1073/pnas.050566797 | doi-access = free | bibcode = 2000PNAS...97.3418B }}</ref> [[Ozone]] sterilization has been studied as a potential method for prion denaturation and deactivation.<ref>{{cite web | url=http://www.hpa.org.uk/hpa/news/articles/press_releases/2005/050414_ozone_sterilizer.htm | title=Ozone Sterilization | date=2005-04-14 | publisher=UK Health Protection Agency | access-date=2010-02-28 |archive-url = https://web.archive.org/web/20070210204514/http://www.hpa.org.uk/hpa/news/articles/press_releases/2005/050414_ozone_sterilizer.htm |archive-date=February 10, 2007 }}</ref> Other approaches being developed include [[thiourea]]-[[urea]] treatment, [[guanidinium chloride]] treatment,<ref>{{cite journal | vauthors = Botsios S, Tittman S, Manuelidis L | title = Rapid chemical decontamination of infectious CJD and scrapie particles parallels treatments known to disrupt microbes and biofilms | journal = Virulence | volume = 6 | issue = 8 | pages = 787–801 | date = 2015 | pmid = 26556670 | pmc = 4826107 | doi = 10.1080/21505594.2015.1098804 }}</ref> and special heat-resistant [[subtilisin]] combined with heat and detergent.<ref>{{cite journal | vauthors = Koga Y, Tanaka S, Sakudo A, Tobiume M, Aranishi M, Hirata A, Takano K, Ikuta K, Kanaya S | title = Proteolysis of abnormal prion protein with a thermostable protease from ''Thermococcus kodakarensis'' KOD1 | journal = Applied Microbiology and Biotechnology | volume = 98 | issue = 5 | pages = 2113–20 | date = March 2014 | pmid = 23880875 | doi = 10.1007/s00253-013-5091-7 | s2cid = 2677641 }}</ref> A number of decontamination reagents have been commercially manufactured with significant differences in efficacy among methods.<ref>{{cite journal |last1=Edgeworth |first1=JA |last2=Sicilia |first2=A |last3=Linehan |first3=J |last4=Brandner |first4=S |last5=Jackson |first5=GS |last6=Collinge |first6=J |title=A standardized comparison of commercially available prion decontamination reagents using the Standard Steel-Binding Assay. |journal=The Journal of General Virology |date=March 2011 |volume=92 |issue=Pt 3 |pages=718–26 |doi=10.1099/vir.0.027201-0 |pmid=21084494 |pmc=3081234}}</ref> A method sufficient for sterilizing prions on one material may fail on another.<ref>{{cite journal | vauthors = Eraña H, Pérez-Castro MÁ, García-Martínez S, Charco JM, López-Moreno R, Díaz-Dominguez CM, Barrio T, González-Miranda E, Castilla J | title = A Novel, Reliable and Highly Versatile Method to Evaluate Different Prion Decontamination Procedures | journal = Frontiers in Bioengineering and Biotechnology | volume = 8 | article-number = 589182 | date = 2020 | pmid = 33195153 | pmc = 7658626 | doi = 10.3389/fbioe.2020.589182 | doi-access = free }}</ref>

Renaturation of a completely denatured prion to infectious status has not yet been achieved; however, partially denatured prions can be renatured to an infective status under certain artificial conditions.<ref>{{cite journal | vauthors = Weissmann C, Enari M, Klöhn PC, Rossi D, Flechsig E | title = Transmission of prions | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 99 | issue = s 4 | pages = 16378–83 | date = December 2002 | pmid = 12181490 | pmc = 139897 | doi = 10.1073/pnas.172403799 | doi-access = free | bibcode = 2002PNAS...9916378W }}</ref>

=== Degradation resistance in nature ===
Overwhelming evidence shows that prions resist degradation and persist in the environment for years, and that [[protease]]s do not degrade them. Experimental evidence shows that ''unbound'' prions degrade over time, while soil-bound prions remain at stable or increasing levels, suggesting that prions likely accumulate in the environment.<ref>{{cite journal | vauthors = Zabel M, Ortega A | title = The Ecology of Prions | journal = Microbiology and Molecular Biology Reviews | volume = 81 | issue = 3 | date = September 2017 | article-number = e00001-17 | pmid = 28566466 | pmc = 5584314 | doi = 10.1128/MMBR.00001-17 }}</ref><ref>{{cite journal | vauthors = Kuznetsova A, Cullingham C, McKenzie D, Aiken JM | title = Soil humic acids degrade CWD prions and reduce infectivity | journal = PLOS Pathogens | volume = 14 | issue = 11 | article-number = e1007414 | date = November 2018 | pmid = 30496301 | pmc = 6264147 | doi = 10.1371/journal.ppat.1007414 | doi-access = free }}</ref> One 2015 study by US scientists found that repeated drying and wetting may render soil bound prions less infectious, although this was dependent on the soil type they were bound to.<ref>{{cite journal | vauthors = Yuan Q, Eckland T, Telling G, Bartz J, Bartelt-Hunt S | title = Mitigation of prion infectivity and conversion capacity by a simulated natural process--repeated cycles of drying and wetting | journal = PLOS Pathogens | volume = 11 | issue = 2 | article-number = e1004638 | date = February 2015 | pmid = 25665187 | pmc = 4335458 | doi = 10.1371/journal.ppat.1004638 | doi-access = free }}</ref>

=== Degradation by living beings ===
Recent studies suggest that scrapie prions can be degraded by diverse cellular mechanisms in the affected animal cell. In an infected cell, extracellular lysosomal PrP<sup>Sc</sup> does not tend to accumulate and is rapidly cleared by the [[lysosome]] via the [[endosome]]. The intracellular portion is harder to clear and tends to build up. The [[Proteasome|ubiquitin proteasome system]] appears to be able to degrade aggregates if they are small enough. [[Autophagy]] plays a bigger role by accepting PrP<sup>Sc</sup> from the ER lumen and degrading it. Altogether these mechanisms allow the cell to delay its death from being overwhelmed by misfolded proteins.<ref name=":1" /> Inhibition of autophagy accelerates prion accumulation whereas encouragement of autophagy promotes prion clearance. Some autophagy-promoting compounds have shown promise in animal models by delaying disease onset and death.<ref name=":1">{{cite journal | vauthors = López-Pérez Ó, Badiola JJ, Bolea R, Ferrer I, Llorens F, Martín-Burriel I | title = An Update on Autophagy in Prion Diseases | language = English | journal = Frontiers in Bioengineering and Biotechnology | volume = 8 | article-number = 975 | date = 2020-08-27 | pmid = 32984276 | pmc = 7481332 | doi = 10.3389/fbioe.2020.00975 | doi-access = free }}</ref>

In addition, [[keratinase]] from [[Bacillus licheniformis|''B. licheniformis'']],<ref>{{cite journal | vauthors = Langeveld JP, Wang JJ, Van de Wiel DF, Shih GC, Garssen GJ, Bossers A, Shih JC | title = Enzymatic degradation of prion protein in brain stem from infected cattle and sheep | journal = The Journal of Infectious Diseases | volume = 188 | issue = 11 | pages = 1782–9 | date = December 2003 | pmid = 14639552 | doi = 10.1086/379664 | bibcode = 2003JInfD.188.1782L }}</ref><ref>{{cite journal | vauthors = Okoroma EA, Purchase D, Garelick H, Morris R, Neale MH, Windl O, Abiola OO | title = Enzymatic formulation capable of degrading scrapie prion under mild digestion conditions | journal = PLOS ONE | volume = 8 | issue = 7 | article-number = e68099 | date = 2013-07-16 | pmid = 23874511 | pmc = 3712960 | doi = 10.1371/journal.pone.0068099 | doi-access = free | bibcode = 2013PLoSO...868099O }}</ref> alkaline [[serine protease]] from ''Streptomyces sp'',<ref>{{cite journal | vauthors = Hui Z, Doi H, Kanouchi H, Matsuura Y, Mohri S, Nonomura Y, Oka T | title = Alkaline serine protease produced by Streptomyces sp. degrades PrP(Sc) | journal = Biochemical and Biophysical Research Communications | volume = 321 | issue = 1 | pages = 45–50 | date = August 2004 | pmid = 15358213 | doi = 10.1016/j.bbrc.2004.06.100 }}</ref> [[subtilisin]]-like pernisine from ''[[Aeropyrum pernix]]'',<ref>{{cite journal | vauthors = Snajder M, Vilfan T, Cernilec M, Rupreht R, Popović M, Juntes P, Serbec VČ, Ulrih NP | title = Enzymatic degradation of PrPSc by a protease secreted from Aeropyrum pernix K1 | journal = PLOS ONE | volume = 7 | issue = 6 | article-number = e39548 | date = 2012 | pmid = 22761822 | pmc = 3386259 | doi = 10.1371/journal.pone.0039548 | doi-access = free | bibcode = 2012PLoSO...739548S }}</ref> alkaline protease from ''[[Nocardiopsis]] sp'',<ref>{{cite journal | vauthors = Mitsuiki S, Hui Z, Matsumoto D, Sakai M, Moriyama Y, Furukawa K, Kanouchi H, Oka T | title = Degradation of PrP(Sc) by keratinolytic protease from Nocardiopsis sp. TOA-1 | journal = Bioscience, Biotechnology, and Biochemistry | volume = 70 | issue = 5 | pages = 1246–8 | date = May 2006 | pmid = 16717429 | doi = 10.1271/bbb.70.1246 | doi-access = free }}</ref> [[nattokinase]] from ''[[Bacillus subtilis|B. subtilis]]'',<ref>{{cite journal | vauthors = Hsu RL, Lee KT, Wang JH, Lee LY, Chen RP | title = Amyloid-degrading ability of nattokinase from Bacillus subtilis natto | journal = Journal of Agricultural and Food Chemistry | volume = 57 | issue = 2 | pages = 503–8 | date = January 2009 | pmid = 19117402 | doi = 10.1021/jf803072r | bibcode = 2009JAFC...57..503H }}</ref> engineered subtilisins from ''B. lentus''<ref>{{cite journal | vauthors = Booth CJ, Johnson CJ, Pedersen JA |date= April 2013 |title=Microbial and enzymatic inactivation of prions in soil environments |url=https://linkinghub.elsevier.com/retrieve/pii/S0038071713000035 |journal=Soil Biology and Biochemistry |volume=59 |pages=1–15 |doi=10.1016/j.soilbio.2012.12.016 |bibcode=2013SBiBi..59....1B |issn=0038-0717|url-access=subscription }}</ref><ref>{{cite journal | vauthors = Dickinson J, Murdoch H, Dennis MJ, Hall GA, Bott R, Crabb WD, Penet C, Sutton JM, Raven ND | title = Decontamination of prion protein (BSE301V) using a genetically engineered protease | journal = The Journal of Hospital Infection | volume = 72 | issue = 1 | pages = 65–70 | date = May 2009 | pmid = 19201054 | doi = 10.1016/j.jhin.2008.12.007 }}</ref> and serine protease from three lichen species<ref>{{cite journal | vauthors = Johnson CJ, Bennett JP, Biro SM, Duque-Velasquez JC, Rodriguez CM, Bessen RA, Rocke TE | title = Degradation of the disease-associated prion protein by a serine protease from lichens | journal = PLOS ONE | volume = 6 | issue = 5 | article-number = e19836 | date = May 2011 | pmid = 21589935 | pmc = 3092769 | doi = 10.1371/journal.pone.0019836 | doi-access = free | bibcode = 2011PLoSO...619836J }}</ref> have been found to degrade PrP<sup>Sc</sup>.

== Fungi ==
{{Main|Fungal prion}}

Proteins showing prion-type behavior are also found in some [[fungus|fungi]], which has been useful in helping to understand mammalian prions. [[Fungal prion]]s do not always cause disease in their hosts.<ref>{{cite journal | vauthors = Lindquist S, Krobitsch S, Li L, Sondheimer N | title = Investigating protein conformation-based inheritance and disease in yeast | journal = Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences | volume = 356 | issue = 1406 | pages = 169–176 | date = February 2001 | pmid = 11260797 | pmc = 1088422 | doi = 10.1098/rstb.2000.0762 }}</ref> In yeast, protein refolding to the prion configuration is assisted by [[Chaperone (protein)|chaperone proteins]] such as [[Hsp104]].<ref name='Aguzzi'>{{cite journal | vauthors = Aguzzi A | title = Unraveling prion strains with cell biology and organic chemistry | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 105 | issue = 1 | pages = 11–12 | date = January 2008 | pmid = 18172195 | pmc = 2224168 | doi = 10.1073/pnas.0710824105 | doi-access = free | bibcode = 2008PNAS..105...11A }}</ref> All known prions induce the formation of an [[amyloid]] fold, in which the protein polymerises into an aggregate consisting of tightly packed [[beta sheet]]s. Amyloid aggregates are fibrils, growing at their ends, and they replicate when breakage causes two growing ends to become four growing ends. The [[incubation period]] of prion diseases is determined by the [[exponential growth]] rate associated with prion replication, which is a balance between the linear growth and the breakage of aggregates.<ref name="Masel 99">{{cite journal | vauthors = Masel J, Jansen VA, Nowak MA | title = Quantifying the kinetic parameters of prion replication | journal = Biophysical Chemistry | volume = 77 | issue = 2–3 | pages = 139–152 | date = March 1999 | pmid = 10326247 | doi = 10.1016/S0301-4622(99)00016-2 | citeseerx = 10.1.1.178.8812 }}</ref>

Fungal proteins that exhibit templated structural change were discovered in the yeast ''[[Saccharomyces cerevisiae]]'' by [[Reed Wickner]] in the early 1990s. For their mechanistic similarity to mammalian prions, they were termed [[yeast prion]]s. Subsequent to this, a prion has also been found in the fungus ''[[Podospora anserina]]''. These prions behave similarly to PrP, but, in general, are nontoxic to their hosts. [[Susan Lindquist]]'s group at the [[Whitehead Institute]] has argued that some fungal prions are not associated with any disease state, but they may have a useful role; however, researchers at the NIH have also provided arguments suggesting that fungal prions could be considered a diseased state.<ref>{{cite journal | vauthors = Dong J, Bloom JD, Goncharov V, Chattopadhyay M, Millhauser GL, Lynn DG, Scheibel T, Lindquist S | title = Probing the role of PrP repeats in conformational conversion and amyloid assembly of chimeric yeast prions | journal = The Journal of Biological Chemistry | volume = 282 | issue = 47 | pages = 34204–12 | date = November 2007 | pmid = 17893150 | pmc = 2262835 | doi = 10.1074/jbc.M704952200 | doi-access = free }}</ref> There is evidence that fungal prions have evolved specific functions that are beneficial to the microorganism that enhance their ability to adapt to their diverse environments.<ref>{{cite journal | vauthors = Newby GA, Lindquist S | title = Blessings in disguise: biological benefits of prion-like mechanisms | journal = Trends in Cell Biology | volume = 23 | issue = 6 | pages = 251–9 | date = June 2013 | pmid = 23485338 | doi = 10.1016/j.tcb.2013.01.007 | hdl-access = free | hdl = 1721.1/103966 }}</ref> Further, within yeasts, prions can act as vectors of [[Epigenetics|epigenetic]] inheritance, transferring traits to offspring without any [[Genome|genomic]] change.<ref>{{cite journal | vauthors = Halfmann R, Lindquist S | title = Epigenetics in the extreme: prions and the inheritance of environmentally acquired traits | journal = Science | volume = 330 | issue = 6004 | pages = 629–632 | date = October 2010 | pmid = 21030648 | doi = 10.1126/science.1191081 | s2cid = 206527151 | bibcode = 2010Sci...330..629H }}</ref><ref>{{cite journal | vauthors = Halfmann R, Jarosz DF, Jones SK, Chang A, Lancaster AK, Lindquist S | title = Prions are a common mechanism for phenotypic inheritance in wild yeasts | journal = Nature | volume = 482 | issue = 7385 | pages = 363–8 | date = February 2012 | pmid = 22337056 | pmc = 3319070 | doi = 10.1038/nature10875 | bibcode = 2012Natur.482..363H }}</ref>

Research into [[fungal prion]]s has given strong support to the protein-only concept, since purified protein extracted from cells with a prion state has been demonstrated to convert the normal form of the protein into a misfolded form ''[[in vitro]]'', and in the process, preserve the information corresponding to different strains of the prion state. It has also shed some light on prion domains, which are regions in a protein that promote the conversion into a prion. Fungal prions have helped to suggest mechanisms of conversion that may apply to all prions, though fungal prions appear to be distinct from infectious mammalian prions in that they lack a cofactor required for propagation. The characteristic prion domains may vary among species&nbsp;– e.g., characteristic fungal prion domains are not found in mammalian prions.{{citation needed|date=January 2023}}

{| class="wikitable"
|+ Fungal prions
|-
! [[Protein]]
! Natural host
! Normal function
! Prion state
! Prion phenotype
! Year identified
|-
| [[Ure2]]p
| ''[[Saccharomyces cerevisiae]]''
| Nitrogen catabolite repressor
| [URE3]
| Growth on poor nitrogen sources
| 1994
|-
| [[Sup35p]]
| ''S. cerevisiae''
| Translation termination factor
| [PSI+]
| Increased levels of nonsense suppression
| 1994
|-
| HET-S
| ''Podospora anserina''
| Regulates [[heterokaryon]] incompatibility
| [Het-s]
| Heterokaryon formation between incompatible strains
|
|-
| Rnq1p
| ''S. cerevisiae''
| Protein template factor
| [RNQ+], [PIN+]
| Promotes aggregation of other prions
|
|-
| Swi1
| ''S. cerevisiae''
| Chromatin remodeling
| [SWI+]
| Poor growth on some carbon sources
| 2008
|-
| Cyc8
| ''S. cerevisiae''
| Transcriptional repressor
| [OCT+]
| Transcriptional derepression of multiple genes
| 2009
|-
| Mot3
| ''S. cerevisiae''
| Nuclear transcription factor
| [MOT3+]
| Transcriptional derepression of anaerobic genes
| 2009
|-
| Sfp1
| ''S. cerevisiae''
| Putative transcription factor
| [ISP+]
| Antisuppression
| 2010<ref name="RogozaT">{{cite journal | vauthors = Rogoza T, Goginashvili A, Rodionova S, Ivanov M, Viktorovskaya O, Rubel A, Volkov K, Mironova L | title = Non-Mendelian determinant [ISP+] in yeast is a nuclear-residing prion form of the global transcriptional regulator Sfp1 | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 107 | issue = 23 | pages = 10573–7 | date = June 2010 | pmid = 20498075 | pmc = 2890785 | doi = 10.1073/pnas.1005949107 | doi-access = free | bibcode = 2010PNAS..10710573R }}</ref>{{contradictory inline|Text did not say about this even as of 2012|date=November 2012}}
|}

== Treatments ==
There are no effective treatments for prion diseases as of 2018.<ref name="pmid28961066">{{cite journal | vauthors = Aguzzi A, Lakkaraju AK, Frontzek K | title = Toward Therapy of Human Prion Diseases | journal = Annual Review of Pharmacology and Toxicology | volume = 58 | issue = 1 | pages = 331–351 | date = January 2018 | pmid = 28961066 | doi = 10.1146/annurev-pharmtox-010617-052745 | url = https://www.zora.uzh.ch/id/eprint/141186/1/Aguzzi_et_al%3B_2017_revised.pdf | access-date = 2020-03-05 | url-status = live | archive-url = https://web.archive.org/web/20200312215409/https://www.zora.uzh.ch/id/eprint/141186/1/Aguzzi_et_al%3B_2017_revised.pdf | archive-date = 2020-03-12 }}</ref> Clinical trials in humans have not met with success and have been hampered by the rarity of prion diseases.<ref name="pmid28961066"/>

Many possible treatments work in the test-tube but not in lab animals. One treatment that prolongs the incubation period in lab mice has failed in human patients diagnosed with definite or probable Variant Creutzfeldt–Jakob disease. Another treatment that works in mice was tried in 6 human patients, all of whom died, before it went out of stock.<ref name=ucl>{{cite web|url=http://www.prion.ucl.ac.uk/clinic-services/research/drug-treatments/|title=Prion Clinic – Drug treatments|date=13 September 2017 |access-date=2020-01-29|archive-date=2020-01-29|archive-url=https://web.archive.org/web/20200129093314/http://www.prion.ucl.ac.uk/clinic-services/research/drug-treatments/|url-status=live}}</ref> There was no significant increase in lifespan, but autopsy suggests that the drug was safe and reached "encouraging" concentrations in the brain and cerebrospinal fluid.<ref>{{cite journal |last1=Mead |first1=Simon |last2=Khalili-Shirazi |first2=Azadeh |last3=Potter |first3=Caroline |last4=Mok |first4=Tzehow |last5=Nihat |first5=Akin |last6=Hyare |first6=Harpreet |last7=Canning |first7=Stephanie |last8=Schmidt |first8=Christian |last9=Campbell |first9=Tracy |last10=Darwent |first10=Lee |last11=Muirhead |first11=Nicola |last12=Ebsworth |first12=Nicolette |last13=Hextall |first13=Patrick |last14=Wakeling |first14=Madeleine |last15=Linehan |first15=Jacqueline |last16=Libri |first16=Vincenzo |last17=Williams |first17=Bryan |last18=Jaunmuktane |first18=Zane |last19=Brandner |first19=Sebastian |last20=Rudge |first20=Peter |last21=Collinge |first21=John |title=Prion protein monoclonal antibody (PRN100) therapy for Creutzfeldt–Jakob disease: evaluation of a first-in-human treatment programme |journal=The Lancet Neurology |date=April 2022 |volume=21 |issue=4 |pages=342–354 |doi=10.1016/S1474-4422(22)00082-5|pmid=35305340 }}</ref>

{{see also|Palliative care}}
While there is no known way to extend the life of a patient with prion disease, some drugs can be prescribed to control specific symptoms of the disease and accommodations can be given to improve quality of life.<ref name=ucl/>

== In other diseases ==
Prion-like domains have been found in a variety of other mammalian proteins. Some of these proteins have been implicated in the ontogeny of age-related neurodegenerative disorders such as [[amyotrophic lateral sclerosis]] (ALS), [[Frontotemporal lobar degeneration|frontotemporal lobar degeneration with ubiquitin-positive inclusions]] (FTLD-U), [[Alzheimer's disease]], [[Parkinson's disease]], and [[Huntington's disease]].<ref name="WalkJuck 2015"/><ref name="Olanow"/><ref name="King 2012">{{cite journal | vauthors = King OD, Gitler AD, Shorter J | title = The tip of the iceberg: RNA-binding proteins with prion-like domains in neurodegenerative disease | journal = Brain Research | volume = 1462 | pages = 61–80 | date = June 2012 | pmid = 22445064 | pmc = 3372647 | doi = 10.1016/j.brainres.2012.01.016 }}</ref><ref name="Goedert">{{cite journal | vauthors = Goedert M | title = NEURODEGENERATION. Alzheimer's and Parkinson's diseases: The prion concept in relation to assembled Aβ, tau, and α-synuclein | journal = Science | volume = 349 | issue = 6248 | article-number = 1255555 | date = August 2015 | pmid = 26250687 | doi = 10.1126/science.1255555 | s2cid = 206558562 }}</ref> They are also implicated in some forms of systemic [[amyloidosis]] including [[AA amyloidosis]] that develops in humans and animals with inflammatory and infectious diseases such as [[tuberculosis]], [[Crohn's disease]], [[rheumatoid arthritis]], and [[HIV/AIDS]]. AA amyloidosis, like prion disease, may be transmissible.<ref>{{cite journal | vauthors = Murakami T, Ishiguro N, Higuchi K | title = Transmission of systemic AA amyloidosis in animals | journal = Veterinary Pathology | volume = 51 | issue = 2 | pages = 363–371 | date = March 2014 | pmid = 24280941 | doi = 10.1177/0300985813511128 | doi-access = free }}</ref> The involvement of abnormal proteins in all of these diseases has given rise to the 'prion paradigm', where otherwise harmless proteins can be converted to a pathogenic form by a small number of misfolded, nucleating proteins.<ref name="Jucker 13">{{cite journal | vauthors = Jucker M, Walker LC | title = Self-propagation of pathogenic protein aggregates in neurodegenerative diseases | journal = Nature | volume = 501 | issue = 7465 | pages = 45–51 | date = September 2013 | pmid = 24005412 | pmc = 3963807 | doi = 10.1038/nature12481 | bibcode = 2013Natur.501...45J }}</ref>

The definition of a prion-like domain arises from the study of fungal prions. In yeast, prionogenic proteins have a portable prion domain that is both necessary and sufficient for self-templating and protein aggregation. This has been shown by attaching the prion domain to a reporter protein, which then aggregates like a known prion. Similarly, removing the prion domain from a fungal prion protein inhibits prionogenesis. This modular view of prion behaviour has led to the hypothesis that similar prion domains are present in animal proteins, in addition to PrP.<ref name="King 2012"/> These fungal prion domains have several characteristic sequence features. They are typically enriched in asparagine, glutamine, tyrosine and glycine residues, with an asparagine bias being particularly conducive to the aggregative property of prions. Historically, prionogenesis has been seen as independent of sequence and only dependent on relative residue content. However, this has been shown to be false, with the spacing of prolines and charged residues having been shown to be critical in amyloid formation.<ref name="Alberti, 2009">{{cite journal | vauthors = Alberti S, Halfmann R, King O, Kapila A, Lindquist S | title = A systematic survey identifies prions and illuminates sequence features of prionogenic proteins | journal = Cell | volume = 137 | issue = 1 | pages = 146–158 | date = April 2009 | pmid = 19345193 | pmc = 2683788 | doi = 10.1016/j.cell.2009.02.044 | bibcode = 2009Cell..137..146A }}</ref>

Bioinformatic screens have predicted that over 250 human proteins contain prion-like domains (PrLD). These domains are hypothesized to have the same transmissible, amyloidogenic properties of PrP and known fungal proteins. As in yeast, proteins involved in gene expression and RNA binding seem to be particularly enriched in PrLD's, compared to other classes of protein. In particular, 29 of the known 210 proteins with an RNA recognition motif also have a putative prion domain. Meanwhile, several of these RNA-binding proteins have been independently identified as pathogenic in cases of ALS, FTLD-U, Alzheimer's disease, and Huntington's disease.<ref name="Eisenberg2012"/>

=== Role in neurodegenerative disease ===
The pathogenicity of prions and proteins with prion-like domains is hypothesized to arise from their self-templating ability and the resulting exponential growth of amyloid fibrils. The presence of [[amyloid]] fibrils in patients with degenerative diseases has been well documented. These amyloid fibrils are seen as the result of pathogenic proteins that self-propagate and form highly stable, non-functional aggregates.<ref name="Eisenberg2012">{{cite journal | vauthors = Eisenberg D, Jucker M | title = The amyloid state of proteins in human diseases | journal = Cell | volume = 148 | issue = 6 | pages = 1188–1203 | date = March 2012 | pmid = 22424229 | pmc = 3353745 | doi = 10.1016/j.cell.2012.02.022 | bibcode = 2012Cell..148.1188E }}</ref> While this does not necessarily imply a causal relationship between amyloid and degenerative diseases, the toxicity of certain amyloid forms and the overproduction of amyloid in familial cases of degenerative disorders supports the idea that amyloid formation is generally toxic.<ref>{{cite journal | vauthors = Ayers JI, Prusiner SB | title = Prion protein - mediator of toxicity in multiple proteinopathies | journal = Nature Reviews. Neurology | volume = 16 | issue = 4 | pages = 187–8 | date = April 2020 | pmid = 32123368 | doi = 10.1038/s41582-020-0332-8 | s2cid = 211728879 }}</ref>

==== TDP-43 ====
Specifically, aggregation of [[TARDBP|TDP-43]], an RNA-binding protein, has been found in ALS/MND patients, and mutations in the genes coding for these proteins have been identified in familial cases of ALS/MND. These mutations promote the misfolding of the proteins into a prion-like conformation. The misfolded form of TDP-43 forms cytoplasmic inclusions in affected neurons, and is found depleted in the nucleus. In addition to ALS/MND and FTLD-U, TDP-43 pathology is a feature of many cases of Alzheimer's disease, Parkinson's disease and Huntington's disease. The misfolding of TDP-43 is largely directed by its prion-like domain. This domain is inherently prone to misfolding, while pathological mutations in TDP-43 have been found to increase this propensity to misfold, explaining the presence of these mutations in familial cases of ALS/MND. As in yeast, the prion-like domain of TDP-43 has been shown to be both necessary and sufficient for protein misfolding and aggregation.<ref name="King 2012"/>

==== RNPA2B1, RNPA1 ====
Similarly, pathogenic mutations have been identified in the prion-like domains of heterogeneous nuclear riboproteins hnRNPA2B1 and hnRNPA1 in familial cases of muscle, brain, bone and motor neuron degeneration. The wild-type form of all of these proteins show a tendency to self-assemble into amyloid fibrils, while the pathogenic mutations exacerbate this behaviour and lead to excess accumulation.<ref name="Kim 2013">{{cite journal | vauthors = Kim HJ, Kim NC, Wang YD, Scarborough EA, Moore J, Diaz Z, MacLea KS, Freibaum B, Li S, Molliex A, Kanagaraj AP, Carter R, Boylan KB, Wojtas AM, Rademakers R, Pinkus JL, Greenberg SA, Trojanowski JQ, Traynor BJ, Smith BN, Topp S, Gkazi AS, Miller J, Shaw CE, Kottlors M, Kirschner J, Pestronk A, Li YR, Ford AF, Gitler AD, Benatar M, King OD, Kimonis VE, Ross ED, Weihl CC, Shorter J, Taylor JP | title = Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS | journal = Nature | volume = 495 | issue = 7442 | pages = 467–473 | date = March 2013 | pmid = 23455423 | pmc = 3756911 | doi = 10.1038/nature11922 | bibcode = 2013Natur.495..467K }}</ref>

====Aβ====
Alzheimer's disease is a form of [[dementia]] that is characterized by the buildup of two abnormal proteins in the brain: [[Aβ]] protein in [[amyloid plaques|Aβ plaques]] and [[tau protein]] in [[neurofibrillary tangles]].<ref name="Long JM 2019">{{cite journal | vauthors = Long JM, Holtzman DM | date = 2019 | title = Alzheimer Disease: An Update on Pathobiology and Treatment Strategies | journal = Cell | volume = 179 | issue = 2 | pages = 312–339 | doi = 10.1016/j.cell.2019.09.001 | pmc = 6778042 | pmid = 31564456 | bibcode = 2019Cell..179..312L }}</ref> Cumulative evidence indicates that abnormalities of Abeta are the earliest [[pathology|pathologic]] sign of Alzheimer's.<ref name="Long JM 2019"/> In experimental animals, scientists found that Aβ can be induced to aggregate to form Aβ plaques and [[cerebral amyloid angiopathy]] by a mechanism that is similar to that underlying prion diseases.<ref name="Jucker 13"/><ref name="Watts JC 2018">{{cite journal | vauthors = Watts JC, Prusiner SB | date = 2018 | title = β-Amyloid Prions and the Pathobiology of Alzheimer's Disease | journal = Cold Spring Harbor Perspectives in Medicine | volume = 8 | issue = 5 | article-number = a023507 | doi = 10.1101/cshperspect.a023507 | pmc = 5554751 | pmid = 28193770}}</ref><ref name="Walker 2024">{{cite journal | vauthors = Walker LC, Jucker M | date = 2013 | title = Seeds of dementia | journal = Scientific American | volume = 308 | issue = 5 | pages = 52–57 | doi = 10.1038/scientificamerican0513-52 | pmc = 10699165 | pmid = 23627220 | bibcode = 2013SciAm.308e..52W }}</ref> Under highly unusual circumstances, Aβ deposition also can be stimulated in humans by the [[iatrogenic]] introduction of abeta 'seeds' (sometimes referred to as 'Aβ prions'<ref name="Watts JC 2018"/>) into the body. Specifically, researchers analyzed people who had been treated with biological materials (such as [[growth hormone]] or [[dura mater]] patches) that had been collected from deceased human donors; they found that some of the recipients developed prion disease, but also that some of them had Aβ plaques and cerebral amyloid angiopathy in the brain.<ref name="Jaun 2015">{{cite journal | vauthors = Jaunmuktane Z, Mead S, Ellis M, Wadsworth JD, Nicoll AJ, Kenny J, Launchbury F, Linehan J, Richard-Loendt A, Walker AS, Rudge P, Collinge J, Brandner S | date = 2015 | title = Evidence for human transmission of amyloid-beta pathology and cerebral amyloid angiopathy | journal = Nature | volume = 525 | issue = 7568 | pages = 247–250 | doi = 10.1038/nature15369 | pmid = 26354483 | bibcode = 2015Natur.525..247J }}</ref><ref name="Kovacs 2016">{{cite journal | vauthors = Kovacs GG, Lutz MI, Ricken G, Strobel T, Hoftberger R, Preusser M, Regelsberger G, Honigschnabl S, Reiner A, Fischer P, Budka H, Hainfellner JA | date = 2016 | title = Dura mater is a potential source of Abeta seeds | journal = Acta Neuropathologica | volume = 131 | issue = 6 | pages = 911–923 | doi = 10.1007/s00401-016-1565-x | pmc = 4865536 | pmid = 27016065}}</ref> This finding suggests that some batches of the biologic agents were contaminated with Aβ seeds, probably because some of the donors had Alzheimer's disease at the time of death. When a very long time had passed following exposure to the contaminated biologic material (30 years or more), some of the affected individuals showed other signs of Alzheimer's disease, including [[neurofibrillary tangles|tauopathy]].<ref name="Jaun 2021">{{cite journal | vauthors = Jaunmuktane Z, Banerjee G, Paine S, Parry-Jones A, Rudge P, Grieve J, Toma AK, Farmer SF, Mead S, Houlden H, Werring DJ, Brandner S | date = 2021 | title = Alzheimer's disease neuropathological change three decades after iatrogenic amyloid-beta transmission | journal = Acta Neuropathologica | volume = 142 | issue = 1 | pages = 211–215 | doi = 10.1007/s00401-021-02326-y | pmc = 8217014 | pmid = 34047818}}</ref><ref name="Banerjee 2024">{{cite journal | vauthors = Banerjee G, Farmer SF, Hyare H, Jaunmuktane Z, Mead S, Ryan NS, Schott JM, Werring DJ, Rudge P, Collinge J | date = 2024 | title = Iatrogenic Alzheimer's disease in recipients of cadaveric pituitary-derived growth hormone | journal = Nature Medicine | volume = 30 | issue = 2 | pages = 394–402 | doi = 10.1038/s41591-023-02729-2 | pmc = 10878974 | pmid = 38287166}}</ref> Researchers emphasize that Alzheimer's is not a contagious disease; rather, the findings in humans support the theory that abnormal Aβ initiates Alzheimer's disease by a 'prion-like' mechanism that originates within the body.<ref name="Jucker 2024">{{cite journal | vauthors = Jucker M, Walker LC | date = 2024 | title = Evidence for iatrogenic transmission of Alzheimer's disease | journal = Nature Medicine | volume = 30 | issue = 2 | pages = 344–345 | doi = 10.1038/s41591-023-02768-9 | pmc = 11492925 | pmid = 38287169}}</ref>

==== Alpha-synuclein ====
{{main|Synucleinopathy}}
Both [[multiple system atrophy]] (MSA) and Parkinson's disease (PD) are associated with misfolded alpha-synuclein. In 2015, it was found that mice engineered to have a susceptible human version of alpha-synuclein become sick with MSA when injected in the brain with the brain homogenate of human MSA patients, but they do not get PD when injected with the brain homogenate of human PD patients. This suggests that the two diseases are different, with MSA being more transmissible.<ref name=pmid26324905/> Misfolded alpha-synuclein from either Parkinson's disease or MSA can be detected by protein misfolding cyclic amplification (PMCA). The two forms, after PMCA, show different levels of fluorescence when bound to thioflavin T. This allows for distinguishing between the two diseases.<ref>{{cite journal |last1=Shahnawaz |first1=M |last2=Mukherjee |first2=A |last3=Pritzkow |first3=S |last4=Mendez |first4=N |last5=Rabadia |first5=P |last6=Liu |first6=X |last7=Hu |first7=B |last8=Schmeichel |first8=A |last9=Singer |first9=W |last10=Wu |first10=G |last11=Tsai |first11=AL |last12=Shirani |first12=H |last13=Nilsson |first13=KPR |last14=Low |first14=PA |last15=Soto |first15=C |title=Discriminating α-synuclein strains in Parkinson's disease and multiple system atrophy. |journal=Nature |date=February 2020 |volume=578 |issue=7794 |pages=273–277 |doi=10.1038/s41586-020-1984-7 |pmid=32025029 |pmc=7066875|bibcode=2020Natur.578..273S }}</ref>

== History ==
In the 18th and 19th centuries, exportation of sheep from Spain was observed to coincide with a disease called [[scrapie]]. This disease caused the affected animals to ''"lie down, bite at their feet and legs, rub their backs against posts, fail to thrive, stop feeding and finally become lame"''.<ref>{{Cite web|title=How Prions Came to Be: A Brief History – Infectious Disease: Superbugs, Science, & Society|url=https://sites.duke.edu/superbugs/module-6/prions-mad-cow-disease-when-proteins-go-bad/how-prions-came-to-be-a-brief-history/|access-date=2021-09-17|language=en-US|archive-date=2021-09-17|archive-url=https://web.archive.org/web/20210917234712/https://sites.duke.edu/superbugs/module-6/prions-mad-cow-disease-when-proteins-go-bad/how-prions-came-to-be-a-brief-history/|url-status=live}}</ref> The disease was also observed to have the long incubation period that is a key characteristic of [[Transmissible spongiform encephalopathy|transmissible spongiform encephalopathies (TSEs)]]. Although the cause of scrapie was not known back then, it is probably the first transmissible spongiform encephalopathy to be recorded.<ref>{{cite journal | vauthors = Ness A, Aiken J, McKenzie D | title = Sheep scrapie and deer rabies in England prior to 1800 | journal = Prion | volume = 17 | issue = 1 | pages = 7–15 | date = December 2023 | pmid = 36654484 | pmc = 9858414 | doi = 10.1080/19336896.2023.2166749 }}</ref>

In the 1950s, [[Daniel Carleton Gajdusek|Carleton Gajdusek]] began research which eventually showed that [[Kuru (disease)|kuru]] could be transmitted to chimpanzees by what was possibly a new infectious agent, work for which he eventually won the 1976 [[Nobel Prize]]. During the 1960s, two London-based researchers, radiation biologist [[Tikvah Alper]] and biophysicist [[John Stanley Griffith]], developed the hypothesis that the [[transmissible spongiform encephalopathy|transmissible spongiform encephalopathies]] are caused by an infectious agent consisting solely of proteins.<ref>{{cite journal | vauthors = Alper T, Cramp WA, Haig DA, Clarke MC | title = Does the agent of scrapie replicate without nucleic acid? | journal = Nature | volume = 214 | issue = 5090 | pages = 764–6 | date = May 1967 | pmid = 4963878 | doi = 10.1038/214764a0 | s2cid = 4195902 | bibcode = 1967Natur.214..764A }}</ref><ref name=Griffith67>{{cite journal | vauthors = Griffith JS | title = Self-replication and scrapie | journal = Nature | volume = 215 | issue = 5105 | pages = 1043–4 | date = September 1967 | pmid = 4964084 | doi = 10.1038/2151043a0 | s2cid = 4171947 | bibcode = 1967Natur.215.1043G }}</ref> Earlier investigations by [[E.J. Field]] into [[scrapie]] and kuru had found evidence for the transfer of pathologically inert polysaccharides that only become infectious post-transfer, in the new host.<ref name="pmid5950508">{{cite journal | vauthors = Field EJ | title = Transmission experiments with multiple sclerosis: an interim report | journal = British Medical Journal | volume = 2 | issue = 5513 | pages = 564–5 | date = September 1966 | pmid = 5950508 | pmc = 1943767 | doi = 10.1136/bmj.2.5513.564 }}</ref><ref name="pmid4175093">{{cite journal | vauthors = Adams DH, Field EJ | title = The infective process in scrapie | journal = Lancet | volume = 2 | issue = 7570 | pages = 714–6 | date = September 1968 | pmid = 4175093 | doi = 10.1016/s0140-6736(68)90754-x }}</ref> Alper and Griffith wanted to account for the discovery that the mysterious infectious agent causing the diseases scrapie and [[Creutzfeldt–Jakob disease]] resisted [[ionizing radiation]].<ref>{{cite journal | vauthors = Field EJ, Farmer F, Caspary EA, Joyce G | title = Susceptibility of scrapie agent to ionizing radiation | journal = Nature | volume = 222 | issue = 5188 | pages = 90–91 | date = April 1969 | pmid = 4975649 | doi = 10.1038/222090a0 | series = 5188 | s2cid = 4195610 | bibcode = 1969Natur.222...90F }}</ref> Griffith proposed three ways in which a protein could be a [[pathogen]]:<ref name=Griffith67/>

In the first [[hypothesis]], he suggested that if the protein is the product of a normally suppressed [[gene]], and introducing the protein could induce the gene's expression, that is, wake the dormant gene up, then the result would be a process indistinguishable from replication, as the gene's expression would produce the protein, which would then wake the gene in other [[cell (biology)|cells]].<ref name=Griffith67/>

His second hypothesis forms the basis of the modern prion theory, and proposed that an abnormal form of a cellular protein can convert normal proteins of the same type into its abnormal form, thus leading to replication.<ref name=Griffith67/>

His third hypothesis proposed that the agent could be an [[antibody]] if the antibody was its own target [[antigen]], as such an antibody would result in more and more antibody being produced against itself.<ref name=Griffith67/> However, Griffith acknowledged that this third hypothesis was unlikely to be true due to the lack of a detectable [[immune response]].<ref name="researchgate.net">{{cite book | vauthors = Bolton D | chapter-url = https://www.researchgate.net/publication/235220355 | chapter = Prions, the Protein Hypothesis, and Scientific Revolutions | veditors = Nunnally BK, Krull IS | title = Prions and Mad Cow Disease | publisher = Marcel Dekker | date = January 1, 2004 | pages = 21–60 | via = ResearchGate | isbn = 978-0-203-91297-3 | access-date = July 27, 2018 | archive-date = March 22, 2022 | archive-url = https://web.archive.org/web/20220322123428/https://www.researchgate.net/publication/235220355_Prions_the_Protein_Hypothesis_and_Scientific_Revolutions | url-status = live }}</ref>

[[Francis Crick]] recognized the potential significance of the Griffith protein-only hypothesis for scrapie propagation in the second edition of his "[[central dogma of molecular biology]]" (1970): While asserting that the flow of sequence information from protein to protein, or from protein to RNA and DNA was "precluded", he noted that Griffith's hypothesis was a potential contradiction (although it was not so promoted by Griffith).<ref>{{cite journal | vauthors = Crick F | title = Central dogma of molecular biology | journal = Nature | volume = 227 | issue = 5258 | pages = 561–3 | date = August 1970 | pmid = 4913914 | doi = 10.1038/227561a0 | s2cid = 4164029 | bibcode = 1970Natur.227..561C }}</ref> The central dogma was later revised, in part, to accommodate [[reverse transcription]] (which both [[Howard Martin Temin|Howard Temin]] and [[David Baltimore]] discovered in 1970).<ref name="pmid27482900">{{cite journal | vauthors = Coffin JM, Fan H | title = The Discovery of Reverse Transcriptase | journal = Annual Review of Virology | volume = 3 | issue = 1 | pages = 29–51 | date = September 2016 | pmid = 27482900 | doi = 10.1146/annurev-virology-110615-035556 | doi-access = free }}</ref>

In 1982, [[Stanley B. Prusiner]] of the [[University of California, San Francisco]], announced that his team had purified the hypothetical infectious protein, which did not appear to be present in healthy hosts, though they did not manage to isolate the protein until two years after Prusiner's announcement.<ref>{{cite journal | vauthors = Taubes G | author-link = Gary Taubes | title =The game of name is fame. But is it science? |journal=Discover |volume=7 |issue=12 |pages= 28–41 |date=December 1986 }}</ref><ref name="Prusiner82">{{cite journal | vauthors = Prusiner SB | title = Novel proteinaceous infectious particles cause scrapie | journal = Science | volume = 216 | issue = 4542 | pages = 136–144 | date = April 1982 | pmid = 6801762 | doi = 10.1126/science.6801762 | url = https://pdfs.semanticscholar.org/f292/b22e2675419c6392a5e55f6b35b1dfc46917.pdf | url-status = dead | s2cid = 7447120 | bibcode = 1982Sci...216..136P | archive-url = https://web.archive.org/web/20200720113942/https://pdfs.semanticscholar.org/f292/b22e2675419c6392a5e55f6b35b1dfc46917.pdf | archive-date = 2020-07-20 }}</ref> The protein was named a prion, for "proteinacious infectious particle", derived from the words protein and infection. When the prion was discovered, Griffith's first hypothesis, that the protein was the product of a normally silent gene, was favored by many. It was subsequently discovered, however, that the same protein exists in normal hosts but in different form.<ref name="pmid26645475">{{cite journal | vauthors = Atkinson CJ, Zhang K, Munn AL, Wiegmans A, Wei MQ | title = Prion protein scrapie and the normal cellular prion protein | journal = Prion | volume = 10 | issue = 1 | pages = 63–82 | date = 2016 | pmid = 26645475 | pmc = 4981215 | doi = 10.1080/19336896.2015.1110293 }}</ref>

Following the discovery of the same protein in different form in uninfected individuals, the specific protein that the prion was composed of was named the prion protein (PrP), and Griffith's second hypothesis, that an abnormal form of a host protein can convert other proteins of the same type into its abnormal form, became the dominant theory.<ref name="researchgate.net"/> Prusiner was awarded the [[Nobel Prize in Physiology or Medicine]] in 1997 for his research into prions.<ref name="nobel">{{cite web | url = http://nobelprize.org/nobel_prizes/medicine/laureates/1997/ | title = The Nobel Prize in Physiology or Medicine, 1997 | access-date = 2010-02-28 | publisher = NobelPrize.org | quote = The Nobel Prize in Physiology or Medicine 1997 was awarded to Stanley B. Prusiner 'for his discovery of Prions - a new biological principle of infection'. | archive-date = 2018-08-09 | archive-url = https://web.archive.org/web/20180809231715/https://www.nobelprize.org/nobel_prizes/medicine/laureates/1997/ | url-status = live }}</ref><ref>{{Cite web| vauthors = Frazer J |title=Prions Are Forever|url=https://blogs.scientificamerican.com/artful-amoeba/prions-are-forever/|access-date=2021-12-28|website=Scientific American Blog Network|language=en|archive-date=2022-01-04|archive-url=https://web.archive.org/web/20220104103748/https://blogs.scientificamerican.com/artful-amoeba/prions-are-forever/|url-status=live}}</ref>

== See also ==
{{Portal|Medicine|Biology}}
* [[Amyloid beta|Beta amyloid]]
* [[Bovine spongiform encephalopathy|Bovine spongiform encephalopathy (BSE)]]
* [[Diseases of abnormal polymerization]]
* [[Kuru (disease)]]
* [[Mad cow crisis]]
* [[Non-cellular life]]
* [[Prion pseudoknot]]
* [[Proteinopathy]]
* [[Subviral agents]]
* [[Tau protein]]

== References ==
{{reflist}}

== External links ==
{{sister project links|d=y|c=category:Prions|species=prion|wikt=prion|b=General_Biology/Classification_of_Living_Things/Viruses|voy=no|v=no|m=no|n=no|mw=no|s=no|q=no|display=Prions}}
* {{cite web |title=Prion Diseases |date=April 22, 2024 |publisher=US Centers for Disease Control and Prevention |url=https://www.cdc.gov/prions/index.html}}[ CDC] – 
* [https://web.archive.org/web/20050309165550/http://www.who.int/zoonoses/diseases/prion_diseases/en/ World Health Organisation] – WHO information on prion diseases
* [http://webarchive.nationalarchives.gov.uk/20090505194948/http://bseinquiry.gov.uk The UK BSE Inquiry]&nbsp;– Report of the UK public inquiry into BSE and variant CJD
* [http://webarchive.nationalarchives.gov.uk/20110316162913/http://www.seac.gov.uk/ UK Spongiform Encephalopathy Advisory Committee (SEAC)]
* {{cite web |url=https://www.hopkinsmedicine.org/health/conditions-and-diseases/prion-diseases |title=Prion Diseases |work=Health: Brain, Nerves and Spine: Infectious Diseases |publisher=Johns Hopkins Medicine }}
* {{cite web |url=https://www.researchgate.net/publication/367434365 |title=Elucidating_the_Mechanism_for_Prion_Formation}}
{{Medical resources
| ICD11 = {{ICD11|XN7AM}} (pathogen), {{ICD11|8E00}}–{{ICD11|8E03}} (diseases)
| ICD10 = {{ICD10|A81}}
| ICD9 = {{ICD9|046}}
| MeshID =
}}
{{Prion diseases}}
{{Self-replicating organic structures}}
{{Organisms et al.}}
{{Gene expression}}
{{Authority control}}

[[Category:Prions| ]]
[[Category:Infectious diseases]]
[[Category:Amyloidosis]]