Originally Posted on Trends in Biomedical Sciences | March 2011
Forty-three years have passed since it was ﬁrst proposed that a prion protein could be the sole component of the infectious agent responsible for the enigmatic prion diseases. Many discoveries have strongly supported the prion protein hypothesis, but only recently has this once heretical hypothesis been widely accepted by the scientiﬁc community.
In the past 3 years, researchers have achieved the ‘Holy Grail’ demonstration that infectious material can be generated in vitro using completely deﬁned components. These breakthroughs have proven that a misfolded protein is the active component of the infectious agent, and that propagation of the disease and its unique features depend on the self-replication of the infectious folding of the prion protein.
In spite of these important discoveries, it remains unclear whether another molecule besides the misfolded prion protein might be an essential element of the infectious agent. Future research promises to reveal many more intriguing features about the rogue prions.
The Mysterious Prion Diseases
Prion diseases are a group of fatal and infectious neurode-generative diseases that affect humans and diverse animal species. The infectious nature of prion diseases was ﬁrst evident more than 70 years ago when accidental transmission of scrapie occurred in sheep. Inoculation against a common virus with a formalin extract of tissue that was unknowingly derived from an animal with scrapie infected nearly 10% of the ﬂock. Scrapie was subsequently transmit-ted experimentally to sheep and later to mice.
In humans, an infectious origin was suspected for kuru, a prion disease identiﬁed in some cannibalistic tribes of New Guinea; a formal demonstration came in 1966 with the transmission of kuru to monkeys. These studies were followed by transmission of Creutzfeldt–Jakob disease (CJD) and Gerstmann–Straussler–Scheinker syndrome, an inherited form of prion disease, to primates.
These discoveries added to the initial ﬁndings that suggested that the infectious agent responsible for these diseases was different from any known form of microorganism, and led to a plethora of research that was aimed at understanding the nature of the agent. A second boost in the prion ﬁeld came when an outbreak of bovine spongiform encephalopathy (BSE) in cattle in the UK was shown to be mediated by prion infection.
Between the discovery of this disease as a prion disorder and the implementation of measures to prevent possible transmission to humans, it is likely that the entire population of the UK and a large part of the European population might have consumed infected meat. These initial concerns were conﬁrmed when a new form of human disease, termed variant CJD, appeared and was convincingly linked to BSE.