Prions and Encephalopathies

Introduction

Digital representation of an incorrectly folded prion protein. Image created by the Mayo Clinic.

“Prion” is the name given to a class of proteins which can cause severe neurological diseases in a host of mammalian species, including humans. These disorders are a result of misfolding of naturally found proteins in host tissue. While the exact mechanisms of transmission from protein to protein are not completely understood, the general mechanism of infection is that existing misfolded proteins cause the same misfolding in these existing normal proteins. These misfolded proteins are extremely resilient– they are resistant to extreme temperatures, both dry and wet, as well as radiation.⁹ The accumulation of diseased prions in mammalian tissues, commonly in the nervous system, causes Transmissible Spongiform Encephalopathies (TSEs). This name reflects the appearance of the infected animal’s tissues after infection – the brain and related tissue resemble sponges because of the disintegration of the tissue by the misfolded protein. In general, these disorders are characterized by a long incubation period, followed by an aggressive and always fatal loss of brain and nervous system function. In addition, these diseases do not induce an inflammatory response in the diseased individual.²

Transmissible Spongiform Encephalopathies in Animals

Include some current research in each topic, with at least one figure showing data.

A domestic sheep in the later stages of Scrapie. Image from http://academics.wellesley.edu/Chemistry/Chem101/aspirin/1mouton%20scrapie.jpg

The Prion Protein and Mechanism of Infection

Include some current research in each topic, with at least one figure showing data.

Interspecific Barriers and Predictors of Susceptibility

Include some current research in each topic, with at least one figure showing data.

Model of a healthy host prion protein proposed by Hagiwara et al. (2012)

Different models of pathogenic prion proteins proposed by Hagiwara et al. (2012)

Genetic Predictions of Susceptibility to TSEs in Carnivores

A study by Stewart et al. (2012) outlined predicted susceptibility to TSEs among carnivore species. TSEs are able to be transmitted successfully to many species through intercerebral injections, yet often only have a select number of target species to which the disease can be transferred through ingestion of the protein. While this study focused primarily on feline and canid transmission of prion diseases, its methods and results are applicable to the examination of oral transmission of the diseases through infected meat in other species. The study reinforces this applicability through proving that the digestion of prion proteins does not vary between carnivores, primates, or hooved animals.⁸

The large finding of the study was a difference of one codon in the prion protein coding sequence between felines and canids - the canine sequence contained either an aspartic acid or glutamic acid at codon 163. This difference is proposed to be the sole reason for the susceptibility of felines to contract TSEs. The researchers use this to explain how FSE occurred in zoos during BSE outbreaks because of infected meat, while no cases of canine prion diseases developed. The study also found the wolverine and pine marten, of all other carnivores, were the only other species to also have the aspartic or glutamic acid at codon 163, suggesting they are resistant to ingested infective BSE proteins.⁸

Aside from this large difference between felines and canids, prion protein polymorphisms within species were investigated as well. Within cats, the margay was found to be the most divergent, while there was absolutely no variation in prion protein sequence in mountain lions. Within feline species, individuals homozygous for a five alanine containing nonapeptide repeat were found to be the most susceptible to prion protein disease. Among canine species, the glutamic acid polymorphism at codon 163 was most common in domestic dogs, while the aspartic acid version was characteristic of gray wolves. Little variation was found in the sequences of black bears as well. This lack of genetic variation in prion protein sequence within both black bears and mountain lions could cause a uniform susceptibility to future TSEs.⁸

Treatment

As mentioned earlier, prions are resistant to extreme temperatures and radiation. However, Baxter et al. (2005) proved the effectiveness of radio frequency gas plasma treatment against misfolded prion proteins. In this study, both surgical instruments and stainless steel spheres were disinfected through radio frequency gas plasma treatment and then analyzed. Surgical instruments were analyzed for organic residues with scanning electron microscopy and x-ray spectroscopy, while the steel spheres were implanted into hamsters to determine the lethality of the treated prions. In the implantation section of this study, all steel spheres were contaminated with misfolded hamster prion proteins. Some of these underwent the radio frequency gas plasma treatment, while others underwent other forms of sanitizing. With these methods the researchers proved that radio frequency gas plasma treatment renders misfolded prion proteins non transmissible.¹

Thus far, there have been several drugs developed which can be used to treat TSEs once the disease causing proteins enter the body. One drug has shown to have great potential – pentose polysulphate. In a study done by Farquhar et al. (1999), mice were injected with or orally consumed pentose polyphosphate before and after exposure to the Scrapie prion. The mice who received the drug prior to exposure experienced a lesser susceptibility to Scrapie, while those who received the drug after exposure had an extended incubation period and a lessening of the symptoms associated with Scrapie. In addition to this, several of the mice who were infected with Scrapie survived.⁴ Another form of treatment has also been developed by researchers in Switzerland and Sweden – luminescent proteins. In their study, luminescent conjugated polymers were applied to brain tissue of mice infected with a prion disease. This resulted in a significant decrease in both the number of misfolded prion proteins present in the tissue, as well as the proteins overall virulence. While these initial results are quite promising, this method of treatment has not yet been perfected for widespread use.³

References

1.^ Baxter, H., Campbell, G., Whittaker, A., Jones, C., Aitken, A., Simpson, A., Casey, M., Bountiff, L., Gibbard, L., and Baxter, R., 2005, Elimination of transmissible spongiform encephalopathy infectivity and decontamination of surgical instruments by using radio-frequency gas-plasma treatment, Journal General Virology, vol 86, pg 2393-2399

2.^ Centers for Disease Control and Prevention, 2013, Prion Diseases, http://www.cdc.gov/ncidod/dvrd/prions/index.htm

3.^ Dillow, C., 2012, First Treatment for Prion-Based Diseases Involves Glowing Polymers, Popular Science, http://www.popsci.com/science/article/2012-04/targeted-polymer-molecules-can-hunt-down-prions-brain, (4/22/2013)

4.^ Farquhar, C., Dickinson, A., and Bruce, M., 1999, Prophylactic potential of pentosan polysulphate in transmissible spongiform encephalopathies, The Lancet, vol 353, pg 117

5.^ Hagiwara, K., Hara, H., and Hanada, K., 2013, Species-barrier phenomenon in prion transmissibility from a viewpoint of protein science, Journal Biochemistry, vol 153, pg 139-145.

6.^ Hodel, L., 2004, Mad Cow Timeline, Mother Earth News,http://www.motherearthnews.com/real-food/mad-cow-timeline.aspx#axzz2REwNFBlC, (4/22/2013)

7.^ Imran, M., Mahmood, S., 2011, An overview of animal prion diseases, Virology Journal, http://www.virologyj.com/content/8/1/493, (4/22/2013)

8.^ Stewart, P., Campbell, L., Skogtvedt, S., Griffin, K., Arnemo, J., Tryland, M., Girling, S., Miller, M., Tranulis, M., and Goldmann, W., 2012, Genetic Predictions of Prion Disease Susceptibility in Carnivore Species Based on Variability of the Prion Gene Coding Region, PLoS ONE, http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0050623, (4/22/2013)

9.^ Yam, P., 2011, Natural Born Prion Killers: Lichens Degrade “Mad Cow” Related Brain Pathogen, Scientific American, http://www.motherearthnews.com/real-food/mad-cow-timeline.aspx#axzz2REwNFBlC, (4/22/2013)

Edited by student of Joan Slonczewski for BIOL 238 Microbiology, 2009, Kenyon College.