User:Joannamasel/draft prion replication
The first hypothesis that tried to explain how prions replicate in a protein-only manner was the heterodimer model.[1] This model assumed that a single PrPSc molecule binds to a single PrPC molecule and catalyzes its conversion into PrPSc. The two PrPSc molecules then come apart and can go on to convert more PrPC. However, Manfred Eigen showed that since PrPC has a very low rate of spontaneous conversion into PrPSc, the heterodimer model requires PrPSc to be an extraordinarily effective catalyst, increasing the rate of the conversion reaction by a factor of around 1015.[2] What is more, despite considerable effort, infectious monomeric PrPSc has never been isolated. Theory and experiments both suggest that PrPSc exists only in aggregated forms such as amyloid, and that prion replication involves cooperativity.
An alternative model assumes that PrPSc exists only as fibrils, and that fibril ends bind PrPC and convert it into PrPSc. If this were all, then the quantity of prions would increase linearly, forming ever longer fibrils. But exponential growth of both PrPSc and of the quantity of infectious particles is observed during prion disease.[3][4][5] This can be explained by taking into account fibril breakage.[6] A mathematical solution for the exponential growth rate resulting from the combination of fibril growth and fibril breakage has been found.[7] The exponential growth rate depends largely on the square root of the PrPC concentration.[7] The incubation period is determined by the exponential growth rate, and in vivo data on prion diseases in transgenic mice match this prediction.[7] The same square root dependence is also seen in vitro in experiments with a variety of different amyloid proteins.[8]
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.[9]
- ^ Cohen FE, Pan KM, Huang Z, Baldwin M, Fletterick RJ, Prusiner SB (1994). "Structural clues to prion replication". Science. 265 (5178): 530–531. doi:10.1126/science.7909169. PMID 7909169.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ Eigen M (1996). "Prionics or the kinetic basis of prion diseases". Biophysical Chemistry. 63 (1): A1-18. doi:10.1016/S0301-4622(96)02250-8. PMID 8981746.
- ^ Bolton DC, Rudelli RD, Currie JR, Bendheim PE (1991). "Copurification of sp33-37 and scrapie agent from hamster brain prior to detectable histopathology and clinical-disease". Journal of General Virology. 72: 2905–2913.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ Jendroska K, Heinzel FP, Torchia M, Stowring L, Kretzschmar HA, Kon A, Stern A, Prusiner SB, DeArmond SJ (1991). "Proteinase-resistant prion protein accumulation in syrian-hamster brain correlates with regional pathology and scrapie infectivity". Neurology. 41: 1482–1490.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ Beekes M, Baldauf E, Diringer H (1996). "Sequential appearance and accumulation of pathognomonic markers in the central nervous system of hamsters orally infected with scrapie". Journal of General Virology. 77: 1925–1934.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ Bamborough P, Wille H, Telling GC, Yehiely F, Prusiner SB, Cohen FE (1996). "Prion protein structure and scrapie replication: theoretical, spectroscopic, and genetic investigations". Cold Spring Harbor Symposium on Quantitative Biology. 61: 495–509. PMID 9246476.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ a b c Masel J, Jansen VAA, Nowak MA (1999). "Quantifying the kinetic parameters of prion replication". Biophysical Chemistry. 77: 139–152. doi:10.1016/S0301-4622(99)00016-2.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ Knowles TPJ, Waudby CA, Devlin GL, Cohen SIA, Aguzzi A, Vendruscolo M, Terentjev EM, Welland ME, Dobson CM (2009). "An Analytical Solution to the Kinetics
of Breakable Filament Assembly". Science. 326: 1533–1537.
{{cite journal}}: line feed character in|title=at position 39 (help)CS1 maint: multiple names: authors list (link) - ^ Masel J, Jansen VAA (2000). "Designing drugs to stop the formation of prions and other amyloids". Biophysical Chemistry. 88: 47–59. doi:10.1016/S0301-4622(00)00197-6. PMID 11152275.