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About the Authors:
Andrew G. Timmes
Affiliation: Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Disease, National Institutes of Health, Hamilton, Montana, United States of America
Roger A. Moore
Affiliation: Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Disease, National Institutes of Health, Hamilton, Montana, United States of America
Elizabeth R. Fischer
Affiliation: Electron Microscopy Unit, Research Technologies Branch, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Disease, National Institutes of Health, Hamilton, Montana, United States of America
Suzette A. Priola
* E-mail: [email protected]
Affiliation: Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Disease, National Institutes of Health, Hamilton, Montana, United States of America
Introduction
The fatal, transmissible neurological diseases scrapie in sheep, Creutzfeldt-Jakob Disease in humans and bovine spongiform encephalopathy in cattle are known as transmissible spongiform encephalopathies (TSEs). They are also known as prion diseases because they are associated with abnormal proteins known as prions that are derived from the mammalian prion protein (PrP). During prion infection, the normal protease-sensitive and soluble host prion protein (PrPC) is converted to an infectious, protease-resistant and insoluble form (PrPSc) which has a different tertiary structure. PrPSc can accumulate over time in tissues of the central nervous system and immune system and, once it reaches pathogenic levels in the brain, trigger a prion disease. PrPSc accumulation is dependent upon the ability of PrPSc to replicate by inducing the conformational conversion of PrPC to more PrPSc, a process known as seeded polymerization (for review see [1]). Detergent insolubility, increased resistance to degradation by proteases, an increased amount of beta-sheet structure relative to PrPC, and especially the ability to self-propagate are all considered hallmarks of infectious prions. However, the mechanisms which underlie the refolding of PrPC into PrPSc remain poorly understood.
Over the last several years, multiple model systems have been developed which are capable of producing infectious PrP in vitro. Techniques such as Protein Misfolding Cyclic Amplification (PMCA), which allows for the self-propagation of PrPSc using uninfected brain homogenate [2] or purified brain-derived PrPC [3] as PrPC substrates as well as other purified or synthetic cofactors [3], have been useful in studying the molecular basis of prion species barriers...