Mad cow disease. This deadly, presently incurable, brain-eating disease has been the cause of many a steak-lover's trepidation. After all, who wants his brain looking like swiss cheese? It is caused by the consumption or spontaneous generation and accumulation of PrPSc - the misfolded form of cellular prion protein (PrP) - and is responsible for several forms of "swiss cheese brain" besides bovine spongiform encephalopathy (affectionately known as mad cow disease), including the sheep-transmitted scrapie and the human form known as Creutzfeldt-Jakob syndrome, among others. Unfortunately for its victims, PrPSc is much more stable than the properly folded form of the protein and is thus resistant to normal methods of protein digestion (i.e. with protease) and is only known to be degradable via incineration of the infected victim. Clearly, this is an undesirable outcome for the individual who has been unfortunate enough to come into contact with such a protein.
As the misfolded PrPSc aggregates, it forms amyloid fibrils, essentially converting the normally folded PrP to the dark side and eventually causing neuronal cell death and ultimately the death of the organism. However, a recent study of methods to stabilize mouse PrPSc species, published in the Journal of Neuroscience, has shown that prion activity can be reduced by trapping partially digested PrP(27-30) with thienyl pyrimidine compounds.
The process of PrP conversion to the abnormally β-sheet-rich PrPSc form is autocatalytic, that is, it happens spontaneously and independently of other types of molecules. In their study, the researchers discovered that the formation of amyloid fibrils may actually be the "result of a protective process to sequester more dangerous soluble oligomers". As a result, rather than attempting to break the prions apart into smaller, supposedly more easily digested pieces, they decided to attempt to isolate them to avoid increasing the infectivity. Using mouse neuroblastoma cell cultures, they performed various drug assays and blotting techniques, including incubation of fibrils with thienyl pyrimidine compound. When all was said and done, they only observed a minimal decrease in the rate of infectivity, but it was a decrease, nonetheless. They concluded that the binding of thienyl pyrimidine-based drugs diverted dimers and trimers of misfolded protein from their pathological aggregation pathway, trapping them thermodynamically in an energy valley where they could no longer fold into their mortality-causing fibril-forming shape.
Though the study was largely inconclusive, it is clear that meaningful advances were made in discovering that the treatment of prion diseases is not as hopeless as we have believed up to this point. Indeed, the thought of finding a cure seems a daunting task, as the mad cow protein only seems to become more stable under most reaction conditions. However, this study has shown that sometime in the not-so-distant future, the mechanism of misfolding will likely be discovered, a cure for a once incurable disease developed, and we will no longer have to fear prions as much as we have in the past. Also, not only does this research have significant implications for those of us who enjoy a good steak or lamb chop, it may also have far-reaching influence on the treatment of other "prionopathies", including Alzheimer's, Parkinson's and Huntington's Diseases. Since these are diseases which affect a significant fraction of the aging population, research in this vein is critical for the progress of gerontological studies as well.