Editing Prion (section)

== 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 = November 1, 2024 }}</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>