The Molecular Mechanisms of Prion Pathogenesis

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The aim of this report is to present the subject of prion proteins, their association and interaction in biological terms, paying particular attention to their molecular mechanisms. Prions are infectious agents responsible for Transmittable Spongiform Encephalopathy (TSE) diseases1, which are debilitating and progressive neurological diseases resulting in both behavioural dysfunction and severe brain tissue damage. These prion proteins are found in different isoforms, and the development from the healthy protein into the misfolded protein is the cause for these diseases is still very much debated. The misfolded protein is responsible aggregates in the neurological and synaptic tissue. However, how exactly this occurs is relatively not known due to the lack of nucleic acid, which is in contrast to all other infectious particle theories (as in all viral, bacterial and parasite agents require nucleic acid in the form of DNA/RNA to replicate and survive)2. The properly folded isoform PrPC (standing for Cellular or Common) is found throughout healthy mammals and their function is still largely unknown. The PrPSc isoform is partially resistant to Protease, and upon digestion by Protinase K produces a core that is protease resistant3. It was first identified as a disease found in sheep called “Scrapie”, first recorded as such, as far back as 1732. Further research found that it was resistant to high heat (a common test to analyse structure) and Formalin (a usual decontamination chemical). In the 1960’s a hypothesis was developed by two researchers (John Stanley Griffith and Tikyah Alper), one a mathematician and the other a radiation biologist (respectively), which stated that some TSE’s are caused by an agent constituted only by prote... ... middle of paper ... ...lymph nodes in uninfected and scrapie-infected mice. J Pathol. 1992;168:413–8 42. Mabbott NA, Young J, McConnell I, Bruce ME. Follicular dendritic cell dedifferentiation by treatment with an inhibitor of the lymphotoxin pathway dramatically reduces scrapie susceptibility. J Virol. 2003;77:6845–54. 43. Beekes M, McBride PA. The spread of prions through the body in naturally acquired transmissible spongiform encephalopathies. FEBS Journal. 2007;274:588–605. 44. EMBO J. 2008 January 23; 27(2): 336–349. The two faces of protein misfolding: gain- and loss-of-function in neurodegenerative diseases Konstanze F Winklhofer,1,a Jörg Tatzelt,1 and Christian Haass 45. Normal host prion protein necessary for scrapie-induced neurotoxicity. Brandner S, Isenmann S, Raeber A, Fischer M, Sailer A, Kobayashi Y, Marino S, Weissmann C, Aguzzi A.Nature. 1996 Jan 25; 379(6563):339-43.

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