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These hints may imply that the problem of animal transmissible spongiform encephalopathies (TSEs) could be more widespread than generally assumed, and may call for drastic measures in the realm of farming. It is not impossible that humans carrying the agent may transmit it horizontally.36 The risks associated with the latter possibility can be met competently only if knowledge is accrued about the mode of transmission of the agent and the mechanism Inhibitors,research,lifescience,medical by which prions reach the brain upon peripheral inoculation into extracerebral sites. The rest of this review article is devoted to analyzing the progress that has been made in these fields. The making of prions A noncommittal, operational definition37 says that the prion is the infectious agent that causes scrapie, BSE, CJD, other TSEs, such as chronic wasting disease

of mule deer and elk, and other less common diseases that affect, for example, exotic ungulates and captive felids. Obviously, although this definition is useful in that it facilitates understanding, it says nothing about the true Inhibitors,research,lifescience,medical physical find more nature of the agent. A very different definition that Inhibitors,research,lifescience,medical has become rather popular among yeast geneticists centers around the structural biology of prions. According to this second definition, prions are proteins that can exist in at least two different conformations, one of which is capable of inducing the conversion of further individual prion molecules from one conformation into the other. Therefore, prion proteins can serve as true genetic elements even if they do not contain informational nucleic acids, in Inhibitors,research,lifescience,medical that they are self-perpetuating and heritable.38 Nineteen years after the original formulation of the prion hypothesis by Stanley Prusiner (Figure 2), and 4 years after he was awarded the Nobel Prize in 1997, there continues to be uncertainty about the question of whether these two definitions coincide in the case of mammalian prions. One further problem is that all amyloids and their precursors

would fit the second definition, yet amyloid proteins themselves Inhibitors,research,lifescience,medical do not appear to be transmissible or infectious in vivo or in cell cultures. In the last few months, we have witnessed breathtaking advances in the understanding of prion phenomena in yeast, and there is no doubt that at least two yeast proteins exist that fulfill no the above definition. It is generally believed that the ultimate experiment proving that a given protein is a prion is “in vitro conversion”: this term defines a cell-free manipulation by which the noncontagious conformation is transformed into a transmissible agent. Ideally, this manipulation should occur without participation of the pathological, transmissible prion, in order to formally exclude the possibility of cross-contamination. Two recent papers have shown that these conditions can be met in the case of the yeast prions identified so far, Sup3539,40 and Ure2p.41,42 Figure 2.