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Structure of the Prion Protein
Structure of the Prion Protein
⬅️ this group analyzed the structure of the protein using ovine PrP.
Chen, W., W Van Der Kamp, M., & Daggett, V. (2014). Structural and Dynamic Properties of the Human Prion Protein. Biophysical Journal, 106, 1152–1163
Structures of PRPC. (2014, December 21). https://www.cureffi.org/2014/12/21/structures-of-prpc/
Kim, I. G., McBride, O. W., Wang, M., Kim, S. Y., Idler, W. W., & Steinert, P. M. (1992). Structure and organization of the human transglutaminase 1 gene. Journal of Biological Chemistry, 267(11), 7710–7717. https://doi.org/10.1016/s0021-9258(18)42573-2
⬅️ This journal article helped me visualize the differences between some of the PrP variants.
Eghiaian, F., Grosclaude, J., Lesceu, S., Debey, P., Doublet, B., Tréguer, E., Rézaei, H., & Knossow, M. (2004). Insight into the PrP C → PrP Sc conversion from the structures of antibody-bound ovine prion scrapie-susceptibility variants. Proceedings of the National Academy of Sciences of the United States of America, 101(28), 10254–10259. https://doi.org/10.1073/pnas.0400014101
Riesner, D. (2003). Biochemistry and structure of PrPC and PrPSc. British Medical Bulletin, 66(1), 21–33. https://doi.org/10.1093/bmb/66.1.21
Benetti, F., & Legname, G. (2015). New insights into structural determinants of prion protein folding and stability. Prion, 9(2), 119–124. https://doi.org/10.1080/19336896.2015.1022023
Mechanisms of Prion Misfolding
Mechanisms of Prion Misfolding
⬅️ fantastic representation of fibril formation. PrP that is prone to unfolding is likely to be incorporated into these PrPsc "solenoids."
Wille, H., & Requena, J. R. (2018). The structure of PRPSC prions. Pathogens, 7(1), 20. https://doi.org/10.3390/pathogens7010020
Baral, P. K., Jiang, Y., Aguzzi, A., & James, M. N. (2019). Transition of the prion protein from a structured cellular form (PrPC) to the infectious scrapie agent (PrPSc). Protein Science, 28(12), 2055–2063. https://doi.org/10.1002/pro.3735
⬅️ the disulfide bond between C179 and C214 is needed for prion conversion. PrPsc, with a reduced S, can attach this disulfide bond and polymerize with the PrP. According to this article, many mutations associated with heritable prion diseases occur near this intramolecular disulfide bridge.
Welker, E., Wedemeyer, W. J., & Scheraga, H. A. (2001). A role for intermolecular disulfide bonds in prion diseases? Proceedings of the National Academy of Sciences of the United States of America, 98(8), 4334–4336. https://doi.org/10.1073/pnas.071066598
Stöhr, J., Weinmann, N., Wille, H., Kaimann, T., Nagel‐Steger, L., Birkmann, E., Panza, G., Prusiner, S. B., Eigen, M., & Riesner, D. (2008). Mechanisms of prion protein assembly into amyloid. Proceedings of the National Academy of Sciences of the United States of America, 105(7), 2409–2414. https://doi.org/10.1073/pnas.0712036105
Honda, R. (2018). Role of the disulfide bond in prion protein amyloid formation: a thermodynamic and kinetic analysis. Biophysical Journal, 114(4), 885–892. https://doi.org/10.1016/j.bpj.2017.12.031
Chen, K., Xu, M., Wedemeyer, W. J., & Röder, H. (2011). Microsecond Unfolding Kinetics of Sheep Prion Protein Reveals an Intermediate that Correlates with Susceptibility to Classical Scrapie. Biophysical Journal, 101(5), 1221–1230. https://doi.org/10.1016/j.bpj.2011.07.024
Specific Pathologies
Specific Pathologies
Creutzfeldt-Jakob Disease
Creutzfeldt-Jakob Disease
⬅️ This video was helpful in understanding the molecular events of cCJD.
Catalyst University. (2019, March 21). Prions | Mechanism of Classical Creutzfeldt-Jakob Disease (CCJD) [Video]. YouTube. https://www.youtube.com/watch?v=ObL8Ba7TWPI
⬅️ superimposition of the wildtype (red) and mutant E200K (blue) PrP proteins. In the mutant, there is no salt bridge formation between E200 and K204, and the distrubution of charges to that of a more positive spread.
Zhang, Y., Świętnicki, W., Zagorski, M. G., Surewicz, W. K., & Sönnichsen, F. D. (2000). Solution structure of the E200K variant of human Prion protein. Journal of Biological Chemistry, 275(43), 33650–33654. https://doi.org/10.1074/jbc.c000483200
Kim, C., Haldiman, T., Cohen, Y., Chen, W., Blevins, J., Sy, M., Cohen, M. L., & Safar, J. (2011). Protease-Sensitive conformers in broad spectrum of distinct PRPSC structures in sporadic Creutzfeldt-Jakob disease are indicator of progression rate. PLOS Pathogens, 7(9), e1002242. https://doi.org/10.1371/journal.ppat.1002242
A Kretzshmar, H., Sethi, S., Foldvari, Z., Windl, O., Querner, V., Zerr, I., & Poser, S. (2003). Iatrogenic Creutzfeldt-Jakob Disease with Florid Plaques. Brain Pathol, 13, 245–249. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8095897/pdf/BPA-13-245.pdf
⬅️ Prominent and Persistent Extraneural Infection in Human PrP Transgenic Mice Infected with Variant CJD - Scientific Figure on ResearchGate. Available from: https://www.researchgate.net/figure/PrPres-plaques-and-spongiform-changes-in-mice-infected-with-vCJD-no-4-late-or-early_fig5_5667715 [accessed 22 Jan, 2024]
⬅️Fig. 2: Brain MRI in individuals with CJD. | Nature Reviews Neurology. (2021, May 10). Nature. https://www.nature.com/articles/s41582-021-00488-7/figures/2
Kuru
Kuru
⬅️ in Kuru, prion aggregates are mainly found in the cerebellum.
McLean, C. (2008). The neuropathology of kuru and variant Creutzfeldt–Jakob disease. Philosophical Transactions of the Royal Society B, 363(1510), 3685–3687. https://doi.org/10.1098/rstb.2008.0086
Fatal Familial Insomnia
Fatal Familial Insomnia
⬅️ FFI severely affects the thalamus, unlike CJD, which has more widespread effects in the brain.
Parchi, P., B Petersen, R., G Chen, S., Autilio-Gambetti, L., Capellari, S., Monari, L., Cortelli, P., Montagna, P., Lugaresi, E., & Gambetti, P. (1998). Molecular Pathology of Fatal Familial Insomnia. Brain Pathol, 8, 539–548. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8098344/pdf/BPA-8-539.pdf
Tan, T. H., Stark, R., Waterston, J., White, O., Thyagarajan, D., & Monif, M. (2020). Genetic prion disease: D178N with 129MV disease modifying polymorphism—a clinical phenotype. BMJ Neurology Open, 2(2), e000074. https://doi.org/10.1136/bmjno-2020-000074
Neurodegenerative Diseases
Neurodegenerative Diseases
⬆️ The different mechanisms by which impaired protein folding and the associated pathways can cause disease.
Valastyan, J. S., & Lindquist, S. (2014). Mechanisms of protein-folding diseases at a glance. Disease Models & Mechanisms, 7(1), 9–14. https://doi.org/10.1242/dmm.013474
Soto, C., & Satani, N. (2011). The intricate mechanisms of neurodegeneration in prion diseases. Trends in Molecular Medicine, 17(1), 14–24. https://doi.org/10.1016/j.molmed.2010.09.001
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