Human Prion Diseases

Human prion diseases are a group of fatal neurodegenerative diseases characterized by a misfolded form of the human prion protein. Symptoms of human prion diseases include ataxia, dementia, involuntary muscle contractions and difficulty swallowing [2]. These diseases can be largely categorized as either Iatrogenic, familial or sporadic. In Iatrogenic cases, the misfolded protein is transferred from one host to another during medical treatment and is extremely rare[5]. Familial cases account for less that 15% of all human prion diseases and are cause by genetic mutations in the prion gene[7]. Sporadic cases are the most common and with the cause of disease yet to be identified. Regardless of the cause of disease, all human prion diseases are fatal and without a cure. Current research focuses on uncovering the molecular players in the pathogenesis of the human prion disease as well as the evolutionary significance of the prion gene using a plethora of different molecular approaches and animal models.


Fig.1 Kuru Victims[16]
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Children affected with Kuru as observed by Dr. Carlton Gajdusek

Kuru [25]
A medical detective story

Kuru is a form of the human prion disease that was endemic to the natives of Papua New Guinea’s Eastern highlands (Fig.1). The natives called Kuru the “laughing death” and thought that the disease was caused by malicious sorcery. As a result, suspected sorcerers could be killed in a rather brutal manner which included biting of their trachea and using stones or clubs to crush their genitalia. Symptoms of the disease include tremor, dementia as well as uncontrolled laughter. The silent incubation time of Kuru can last about 10 years and the victim usually dies 12 month after the onset of clinical symptoms. In 1957, Nobel Laureate Dr. Carleton Gajdusek first reported Kuru to the Western world. At the time, similarities between Kuru and the mammalian prion disease in sheep known as “scrapie” were quickly recognized by many, including William Hadlow. A few years later, Gajdusek and his colleagues showed that Kuru could be transmitted from humans to chimpanzees and determined that the causative agent of the disease was likely transmitted among tribesmen through their practice of endocannabilism. Kuru, a nearly extinct disease in the present, has helped scientists understand many aspects of more common human prion diseases such as Creutzfeld-Jakob disease and fatal familial insomnia [1].

Clinical and pathological presentation of Human Prion Diseases

Fig.2 Spongiform degeneration[17]
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Spongiform degeneration within the straitum of CJD patient

Clinical presentation of Creutzfeld-Jakob Disease (CJD) is variable but typically involves a progressive decline of cognitive and motor function leading to ataxia, dementia, involuntary muscle contraction and difficulty swallowing. vCJD, or mad cow disease in humans, has a earlier age of onset and a long disease progression compared to other forms of the prion disease. Sporadic CJD and dura mater graft-associated Iatrogenic CJD most often result in dementia while Kuru and human growth-hormone associated Iatrogenic CJD are diseases that largely affect the cerebellum, leading to motor dysfunction [2]. The defining pathological features of CJD are gliosis and the loss of neurons. This results in the formation of microscopic “holes” within the brain tissue in a process termed “spongiform degeneration (Fig.2).” The presence of amyloid plaques is restricted to a vCJD and Kuru[3].

General mechanism of propagation and sporadic cases

Fig.3 Mechanism of propagation[18]
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The seeding and refolding models of templated conversion

Prion aggregation[26]
From normal to scrapies

In 1982, Dr. Stanley Prusiner proposed the prion hypothesis which predicted that the disease causing agent in human prion diseases was the prion protein itself and that the disease form of prion protein is derived from a misfolded form of the endogenous wildtype prion protein. Furthermore, a model know as “Templated-Conversion” was later proposed and postulates that the misfolded prion protein is able to convert endogenous prion protein into the disease causing form and thus explains how prion disease can self propagate (Fig. 3). These two theories have withstood the rigorous test of time even to this date. This disease causing form of the prion protein is thought to form aggregates which are toxic to neurons. Sporadic prion diseases account for over 85% of all human prion disease with the cause of disease yet to be identified. Currently, there are 5 subtypes of sporadic prion disease classified based on clinical, histological and molecular markers. One of such markers is the natural polymorphism that exists at codon 129, which can be a valine or methionine residue. Three of these subtypes largely affect cognitive function whereas the other two are affect the normal functioning of the cerebellum [4].

Iatrogenic transmission and sterilization of surgical tools

Iatrogenic prion disease defines a very small subset of patients who have inadvertently acquired the disease causing agent in a medical procedure. One of the methods of transmission is via blood transfusion. During the "mad cow"disease epidemic, one of the first human victims of mad cow disease, also known as variable Creutzfeld-Jakob Disease, was reported to have contracted the disease particle after receiving blood from a donor who had vCJD. Other individuals were infected with prion disease after receiving an intramuscular dose pituitary growth hormone, presumably derived from an affected individual[5]. Corneal surgery and neurosurgical procedures have also resulted in the transmission of the prion disease agent from host to recipient, likely through the use of contaminated surgical tools. The disease causing form of the prion protein is resistant to heat and proteolysis. As a result, standard hospital sterilization protocols have been shown to be ineffective in dealing with the prion disease protein. Furthermore, current procedures for sterilization involve the use of bleach and alkaline agents, which can be very damaging to the instruments. Despite low rates of Iatrogenic CJD, more effective methods of sterilization would help alleviate some of the public’s concern for the safety of neurosurgical and other medical procedures [6].

Familial cases and Prion disease outside the CNS

Fig.4 Mutation in PRNP[19]
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Pathogenic mutations within the prion gene

Fig.5 Pedigree of novel prion mutation[20]
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Novel prion mutation that is associated with diarrhea and autonomic neuropathy

The human prion gene (PRNP) is located on chromosome 20 and has two exons. The second exon itself encodes the complete prion protein of 253 amino acid residues. The two types of genetic mutations in the PRNP gene that have been linked to familial prion diseases are missense point mutations that change the identity of the amino acid residue or larger Octapeptide Repeat (OPR) insertions or deletions. Recent studies have shown that insertion of 1 to 7 ORP into the transcript have been found to associate with CJD (Fig. 4). In terms of point mutations, most of them have only been identified within a single individual or within small families [7]. However, a recent study by Mead et al. has identified a novel truncation mutation within the transcript of the prion gene in a large British Family. In this study, the authors used a multi-faceted approach to identify a PRNP Y163X mutation that is associated with symptoms of diarrhea, autonomic neuropathy and peripheral polyneuropathy (Fig. 5). Furthermore, the prion protein was observed in many organs outside the CNS including the bowel and peripheral nerves. In terms of the pathological findings, amyloid plaques which are normally restricted to Kuru and vCJD have been frequently identified within late stage diseased individuals carrying the Y163X mutation in the prion gene. Fortunately, this disease was not able to be transmitted to mice. In summary, the authors identified a form of the human prion disease that is largely a peripheral disease, different from the other forms of familial CJD [8].

Structural and functional similarities between Prion and ZIP

Fig.6 Prion and LIV-1[21]
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Similarities between the prion protein and the ectodomain of the LIV-1 ZIP transporter

The ZIP family consists of a group of metal iron transporters that are capable of transporting zinc and other heavy metals into the cell [9]. In a recent proteomic screen, two ZIP family members ZIP10 and ZIP6 were identified as potential molecular interactors of the prion protein at the cell surface. Further investigations revealed that prion proteins are structurally similar to ZIP10 and ZIP6 in the extracellular domain. For example, both the ZIP proteins and the prion proteins contain this highly conserved Cystein Flanked Core (CFC) domain within its extracellular domain. However, the ZIP proteins have a transmembrane domain whereas the prion protein encodes a GPI anchor (Fig. 6) [10]. Functionally, the ZIP transporters contain a Prion-like ectodomain. Under conditions of cation starvation, this ectodomain is proteolytically removed to increase the transport of cations into the cell through the ZIP transporters. This proteolytic cleavage of the Prion-like ectodomain was also observed in a subset of ZIP transporter in the brain of prion-infected mice [11]. These structural and functional similarities suggest a common evolutionary origin.

Evolution of the Prion gene in a retroviral-mediated process

Fig.7 Evolution of the Prion gene[22]
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Model for the evolution of the prion gene from its ZIP ancestor

The prion founder gene is thought to have evolved from the ZIP family in a two step mechanism. Approximately 1 billion years ago, during the period in which metazoans first emerged, it is thought that a Cystein Flanked Core (CFC) domain was inserted into an ancient ZIP gene. Alternatively, this CFC domain could have evolved independently de novo. 500 million years later, during the time of vertebrate speciation, this ancient ZIP gene with its CFC domain insert becomes transcribed, spliced and reinserted into the genome by the actions of a retrovirus. Since this gene is inserted downstream of a functional promoters, the gene is fully functional and becomes the prion funder gene (Fig. 7). This explains why the ZIP proteins have a complex exon intron structure where as the prion gene is encoded by a single exon [12].

Mouse models-knock out and knock in

Fig.8 Prion and Myelin maintanence[23]
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Prion knockout mice have a deficiency in peripheral myelin maintanence (wild type-left, KO-right)

The most striking phenotype of a prion knockout mouse is that it is resistant to prion infection. Reintroducing the prion gene into a knock-out mouse restores prion infectivity. Furthermore, it has been shown that a expression of a fragment of the prion protein, PrPΔ23–88 and Δ141–176, is sufficient for a mice to be infected with prion disease. Other than resistance to prion infection, knock out of the prion gene in both embryonic models and in the adult brains has no other major phenotypes that affect the longevity or fertility of the mice in most reports [13]. However, a recent paper showed that knock out of prion proteins specifically in neurons affect proper myelin maintenance in the peripheral nervous system (Fig. 8) [14].
Mice overexpressing the human prion protein with the valine residue at position 129 are more susceptible to developing sporadic CJD compared to the mice overexpressing the human prion protein with the methionine residue at position 129. Note that this is a naturally occurring polymorphism at position 129. Mice expressing the bovine form of the prion protein (vCJD model) are much more infectious compared to those expressing the human form of the prion protein. A transgenic model expressing a human prion protein with a proline to leucine substitution at position 102 has been one of the most studied models of familial CJD. These mice do develop neurological defects but the mutated form of the protein is not detected at high levels within the brain. In addition, these mice rarely transmit the symptoms they experience to wild type mice housed in the same cage [13].

Potential treatments-polyanionic compounds, antibiotics and immunotherapy

Fig.9 Therapeutic mechanisms[24]
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Potential therapeutic agents targeting different sites within the prion pathogenesis pathway

Current therapies for prion disease take a multitude of approaches (Fig. 9). Some therapies aim to prevent the conversion of wildtype prion protein to the disease causing form. Others are aimed at degrading or clearing the prion disease protein from cells or interfering with the cell surface localization of the prion protein. Polyanionic compounds such as pentosan polysuphate (PPS) interfere with the interaction between the prion protein and endogenous heparin sulfate proteoglycans at the cell surface. Administration of this compound has been shown to prolong the incubation time of mice infected with prion disease and thus slowing the disease progression. Tetracycline, a well known antibiotic, increased the survival rates of mice with prion disease. The mechanism of action is thought to be by enhancing the proteolytic degredation of prion protein peptides by Proteinase K. Immunotherapies involve using antibodies to target the prion protein and was shown to have an effect in reducing the conversion of wildtype prion proteins to the disease causing form as well as preventing the oligomerization into prion toxic aggregates [15].

1. Ahmad, S. I. (2012). Kuru: The First Prion Disease. Neurodegenerative diseases (pp. 143-153). New York: Landes Bioscience.
2. Head, M., & Ironside, J. (2012). Review: Creutzfeldt–Jakob disease: prion protein type, disease phenotype and agent strain. Neuropathology and Applied Neurobiology, 38(4), 296-310.
3. Head, M. W., & Ironside, J. W. (2012). The contribution of different prion protein types and host polymorphisms to clinicopathological variations in Creutzfeldt-Jakob disease. Reviews in Medical Virology, 22(4), 214-229.
4. Puoti, G., Bizzi, A., Forloni, G., Safar, J., Tagliavini, F., & Gambetti, P. (2012). Sporadic human prion diseases: molecular insights and diagnosis. The Lancet Neurology, 11(7), 618-628.
5. Barrenetxea, G. (2012). Iatrogenic prion diseases in humans: an update. European Journal of Obstetrics & Gynecology and Reproductive Biology, 165(2), 165-169.
6. Thomas, J. G., Chenoweth, C. E., & Sullivan, S. E. (2013). Iatrogenic Creutzfeldt-Jakob disease via surgical instruments. Journal of Clinical Neuroscience, 20(9), 1207-1212.
7. Capellaru, S., Strammiello, R., Saverioni, D., Kretzschmar, H., & Parchi, P. (2011). Genetic Creutzfeldt–Jakob disease and fatal familial insomnia: insights into phenotypic variability and disease pathogenesis. Acta Neuropathologica, 121(1), 21-37.
8. Mead, S., Sandberg, M. K., Holton, J. L., Revesz, T., Sharps, B., Al-Doujaily, H., et al. (2013). A Novel Prion Disease Associated with Diarrhea and Autonomic Neuropathy. New England Journal of Medicine, 369(20), 1904-1914.
9. Guerinot, M. L. (2000). The ZIP family of metal transporters. Biochimica et Biophysica Acta (BBA) - Biomembranes,1465(1-2), 190-198.
10. Schmitt-Ulms, G., Ehsani, S., Watts, J. C., Westaway, D., Wille, H., & Poon, A. F. (2009). Evolutionary Descent of Prion Genes from the ZIP Family of Metal Ion Transporters. PLoS ONE, 4(9), e7208.
11. Ehsani, S., Mehrabian, M., Pocanschi, C. L., & Schmitt-Ulms, G. (2012). The ZIP-prion connection. Prion, 6(4), 317-321.
12. Ehsani, S., Tao, R., Pocanschi, C. L., Ren, H., Harrison, P. M., Schmitt-Ulms, G., et al. (2011). Evidence for Retrogene Origins of the Prion Gene Family. PLoS ONE, 6(10), e26800.
13. Wadsworth, J., Asante, E., & Collinge, J. (2010). Review: Contribution of transgenic models to understanding human prion disease. Neuropathol Appl Neurobiol., 36(7), 576-597.
14. Bremer, J., Weis, J., Aguzzi, A., Nave, K., Toyka, K. V., Steele, A. D., et al. (2010). Axonal prion protein is required for peripheral myelin maintenance. Nature Neuroscience, 13(3), 310-318.
15. Panegyres, K., & Armari, E. (2013). Therapies for human prion diseases. Am J Neurodegener Dis., 2(3), 176-186.
16. Adapted from “Kuru: The First Prion Disease.” by Ahmad et al., 2012. Neurodegenerative diseases, p.143-153. Copyright 2011 by Landes Bioscience.
17. Adapted from “Frontal Cortex Online Courses” Retrieved March 24 2014 from: Copyright 2004 by Frontal Cortex Inc.
18. Adapted from “Prions: health scare and biological challenge.” by Aguzi et al., 2001. Nature Reviews Molecular Cell Biology 2, p.118-126. Copyright 2001 by Macmillan Publishers limited.
19. Adapted from “Genetic Creutzfeldt–Jakob disease and fatal familial insomnia: insights into phenotypic variability and disease pathogenesis.” by Capellaru et al., 2011. Acta Neuropathologica 121(1), p.21-37. Copyright 2011 by Springer.
20. Adapted from “A Novel Prion Disease Associated with Diarrhea and Autonomic Neuropathy.” By Mead et al., 2013. New England Journal of Medicine 369(20), p.1904-1914. Copyright 2013 by Massachusetts Medical Society .
21. Adapted from “The ZIP-prion connection.” By Ehsani et al., 2012. Prion 6(4), 317-321. Copyright 2012 by Landesbioscience .
22. Adapted from “Evidence for Retrogene Origins of the Prion Gene Family.” By Ehsani et al., 2011. PLOS ONE 6(10), e26800. Copyright 2011 by PLOS.
23. Adapted from “Axonal prion protein is required for peripheral myelin maintenance.” By Bremer et al., 2010. Nature Neuroscience 13(3), p.310-318. Copyright 2011 by Macmillan Publishers limited.
24. Adapted from “Therapies for human prion diseases.” By Panegyres et al., 2013, Neurodegeneration Discoveries 2(3), p.176-186. Copyright 2013 by e-Century Publishing Corporation.

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