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Abstract & Commentary
Synopsis: The generation of disease-producing prions requires less stringent conditions than previously thought.
Source: Derkatch IL, et al. Prions affect the appearance of other prions: The story of [PIN(+)]. Cell. 2001;106:171-182.
While studying the yeast model, Derkatch and colleagues at the University of Illinois in Chicago discovered that the existence of 1 type of prion could enhance the spontaneous appearance of other types of prions. Derkatch et al had previously established that the yeast non-Mendelian trait [PIN(+)] is required for the de novo appearance of the [PSI(+)] prion. In this study, they showed that the presence of prions formed by Rnq1 or Ure2 is sufficient to make cells [PIN(+)]. This, combined with other work they performed, suggests the existence of a general mechanism by which the appearance of prions is enhanced by heterologous prion aggregates. Since most cases of Creutzfeldt-Jakob disease (CJD) have no known origin, Derkatch et al feel that this may be how prions first appear in humans.
Comment by Thomas G. Schleis, MS, RPh
The Prion diseases constitute an unusual group of neurodegenerative disorders. Similar in many ways to diseases such as Alzheimer’s disease and amyotrophic lateral sclerosis (ALS), they differ in their transmissible natures. The prion diseases also demonstrate that the expression of diverse disease phenotypes is possible from a common etiologic factor. Prion diseases are of concern because there are no definitive tests available for detecting the infectious agent, they have relatively long incubation periods, and the inevitable result is death.
The human prion diseases include kuru, sporadic Creutzfeldt-Jakob disease (sCJD), familial CJD (fCJD), iatrogenic CJD (iCJD), Gerstmann-Straussler-Scheinker (GSS) disease, fatal insomnia (FI), and more recently, new variant CJD (nvCJD or vCJD). Animal prion disease includes transmissible mink encephalopathy (TME), chronic wasting disease (CWD) of deer and elk, feline spongiform encephalopathy (FSE), and bovine spongiform encephalopathy (BSE), among others. While most of these animal diseases are presumed to result from ingestion of animal byproducts contaminated with sheep scrapie, CWD appears to be a naturally occurring disease of North America.
The transmissible nature of prion disease was first demonstrated experimentally in 1936 when Cuille and Chelle transmitted scrapie to a healthy goat by the intraocular administration of scrapie-infected spinal cord.1 Thirty years later, kuru, a disease transmitted among the Fore people of New Guinea through cannibalism, was experimentally transmitted to chimpanzees.2 While the etiologic agent was first thought to be viral, the current predominant theory is that a small protein is responsible.3,4
How a small protein may be a transmissible pathogen has also been extensively studied. It appears that the prion protein (PrP) exists in 2 major isoforms or stuctures: the nonpathogenic or cellular form, designated PrPc, and the pathogenic form, designated PrPSc. Both have the same amino acid sequence, but PrPc is predominantly helical whereas PrPSc contains at least 40% of a pleated sheet structure. PrPSc has different solubility characteristics than PrPc and is more resistant to proteases.5 The potential mechanism as to how the conversion from PrPc to PrPSc is initiated, involves a germ line mutation of the human prion protein gene (PRNP), a somatic mutation within a particular neuron, and the resultant conversion of PrPc to PrPSc. Once this event takes place, the PrPSc appears to act as a template by which more PrPc is converted to PrPSc, hence the "infectious" process. In the article reviewed here, it would appear that there is not a complete specificity for one type of prion over another and that spontaneous mutations can occur.
CJD has been the most common human prion disease that has appeared in recent literature. Confirmed transmission of CJD in humans has only been shown to occur with corneal and dura mater transplants or human pituitary growth hormone injections. Nevertheless, blood and blood products that are administered intravenously are immediately recalled if a donor is determined to have vCJD, but not sCJD, fCJD, or iCJD. This is done as a precautionary measure because of its more rapid onset of vCJD vs. other CJDs and the possible association of vCJD to BSE, or Mad Cow disease. Because of the resistance of prions to normal antiviral inactivation steps that are used with such blood products as intravenous immunoglobulins (IVIG) and albumin, manufacturers are attempting to develop methods for the testing and removal of prions from these preparations. So far this has proven to be quite difficult.
Prion disease is an area that requires a great deal of additional research in order to identify the mechanism of transmission and develop methods of prevention and treatment. While the greatest press have been given to the epidemic of mad cow disease in the United Kingdom and CJD disease in the United States, the presence of prion disease is worldwide and will continue to be an area of active research.
1. Cuillé J, Chelle PL. Experimental transmission of trembling to the goat. C R Seances Acad Sci. 1939; 208:1058-1060.
2. Gajdusek DC, et al. Experimental transmission of a kuru-like syndrome to chimpanzees. Nature. 1966; 209:794-796.
3. Alper T, et al. The exceptionally small size of the scrapie agent. Biochem Biophys Res Commun. 1966; 22:278-284.
4. Alper T, et al. Does the agent of scrapie replicate without nucleic acid? Nature. 1967;214:764-766.
5. Safar J, et al. Conformational transitions, dissociation, and unfolding of scrapie amyloid (prion) protein. J Biol Chem. 1993;268:20276-20284.
Dr. Schleis, Director of Pharmacy Services, Infections Limited, Tacoma, Wash., is Associate Editor of Infectious Disease Alert.