User:Eliška Koutná/Sandbox 3
From Proteopedia
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The fundamental event in propagation of the infectious form lies in the PrPSc template-directed misfolding of the natural form into the pathogenic, β-sheet-rich version of itself <ref name="pan" />. This process is now widely accepted as a current prion theory, and the most striking fact is that this action lacks any nucleic acid template <ref name="sigurdson" />. However, the replication cycle of PrPSc does need the PRNP gene to direct PrPC synthesis. Also, the interaction between the pathogenic and physiological form must be quite specific to propagate the conversion. The replication process itself can be explained by stochastic fluctuations in the PrPC structure, that would create the intermediate form, PrP*. This partially unfolded monomer can then switch back to the natural conformation, adopt a PrPSc one, or be degraded. Normally, there is an equilibrium between the PrPC and PrP* states which favors the physiological one. Depending on the specific cause of the disease, the PrP* state can adopt a PrPSc conformation either upon contant with a dimer of this infectious form by forming a heteromultimer which is further converted into a homomultimer of PrPSc, or through encounter with another PrP* molecule. This PrP*/PrP* dimer can then form an infectious dimer and initiate the replication cycle <ref name="cohen">DOI 10.1126/science.7909169</ref> <ref name="cohen&prusiner" />. It has been found that certain host-specific RNAs can assist with the conversion into the pathogenic form <ref>DOI 10.1038/nature01979</ref>. | The fundamental event in propagation of the infectious form lies in the PrPSc template-directed misfolding of the natural form into the pathogenic, β-sheet-rich version of itself <ref name="pan" />. This process is now widely accepted as a current prion theory, and the most striking fact is that this action lacks any nucleic acid template <ref name="sigurdson" />. However, the replication cycle of PrPSc does need the PRNP gene to direct PrPC synthesis. Also, the interaction between the pathogenic and physiological form must be quite specific to propagate the conversion. The replication process itself can be explained by stochastic fluctuations in the PrPC structure, that would create the intermediate form, PrP*. This partially unfolded monomer can then switch back to the natural conformation, adopt a PrPSc one, or be degraded. Normally, there is an equilibrium between the PrPC and PrP* states which favors the physiological one. Depending on the specific cause of the disease, the PrP* state can adopt a PrPSc conformation either upon contant with a dimer of this infectious form by forming a heteromultimer which is further converted into a homomultimer of PrPSc, or through encounter with another PrP* molecule. This PrP*/PrP* dimer can then form an infectious dimer and initiate the replication cycle <ref name="cohen">DOI 10.1126/science.7909169</ref> <ref name="cohen&prusiner" />. It has been found that certain host-specific RNAs can assist with the conversion into the pathogenic form <ref>DOI 10.1038/nature01979</ref>. | ||
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| + | == '''Pathogenesis''' == | ||
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| + | In the case of infectious/iatrogenic diseases, pathogenic prion proteins enter the body alimentary via ingestion of affected neural tissues, or via infected materials and tissues such as during blood transfusions, corneal transplants or dura mater grafts. In this case, the exogenous PrPSc form would serve as a template to promote the conversion of PrP* and, due to its insolubility, make this exponential conversion process irreversible <ref name="cohen" />. | ||
| + | Genetic, or inherited cause comprise the familial TSEs and comes from DNA mutations in the PRNP gene, which then produces mutant, unstable forms of PrPC with higher tendency of folding into the PrP* form. This further increases the chance of PrPSc forming <ref name="cohen&prusiner" />. The mutations in PRNP are autosomal dominant, highly penetrant, and consist of missense mutations, insertions and deletions <ref name="sigurdson" />. With higher probability of protein misfolding in the old age, they usually incite disease onset in the late decades of life and ultimately lead to accumulation of prion proteins and rapid development of neurodegenerative disease <ref name="khanam">DOI 10.1016/j.ejmech.2016.08.006</ref>. | ||
| + | Concerning sporadic form of prion disease, the concentration of PrPSc may eventually reach a threshold level upon which a positive feedback loop would stimulate the formation of PrPSc. It requires solely a rare molecular event of formation of the PrP*/PrP* complex, or a somatic cell mutation followed by the mechanism of the initiation of inherited disease. Once formed, the replication cycle is primed for subsequent conversion <ref name="cohen" /> <ref name="cohen&prusiner" />. | ||
| + | Ultimately, in all cases this leads to PrPSc polymerization, forming a rod-like structures and amyloid plaques. | ||
== References == | == References == | ||
<references/> | <references/> | ||
Revision as of 15:03, 15 May 2019
Prions
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