Prion Disease Update
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Prion diseases, or transmissible spongiform encephalopathies (TSEs) as they are sometimes called, are a group of related neurodegenerative disorders where there is so-called spongiform degeneration of the brain. Under the microscope, sections of affected brain tissue look like a sponge. Such diseases include scrapie in sheep, bovine spongiform encephalopathy (BSE or mad cow disease) in cattle, chronic wasting disease in deer and elk and the human diseases such as Creutzfeldt–Jakob disease (CJD). A unique feature of these diseases is that they can be inherited, arise spontaneously or may be acquired through infection. The infectious forms of prion diseases, TSEs, are inevitably fatal and no effective therapy is available.
Kuru was an extremely rare prion disease found exclusively found among people from New Guinea, who practiced a form of ritual cannibalism in which the brains of dead relatives were eaten as part of a funeral in order to honour the dead. Kuru causes neurodegenerative changes similar to Creutzfeldt-Jakob disease and other TSEs. More recently, transmission of prion-contaminated growth hormones to children with growth deficiencies resulted in over 250 patients contracting Creutzfeldt-Jakob disease (CJD). Over the past 20 years more than 280,000 cattle have contracted bovine spongiform encephalopathy (BSE). During the same period, transmission of BSE to humans is believed to have caused over 150 cases of a new variant of CJD (vCJD). The possibility that millions of people could have come into contact with BSE-contaminated meat sparked a widespread public health scare that is still relevant today. In addition, the possibility of human-to-human prion transmission by blood transfusions alerted health authorities to the importance of vigourously controlling the origin and quality of donated blood.
According to what is known as the protein-only hypothesis, the critical event in the pathogenesis of prion disease is the conversion of the normal, cellular form of the prion protein (PrPC) into an aberrantly folded, disease-associated form known as PrPSc. Inherited forms of prion disease are caused by mutations in the PrP gene (PRNP) which is located on human chromosome 20. Several pathogenic mutations in PrP have now been described, leading to various types of inherited disease, such as Gerstmann-Sträussler-Scheinker syndrome (GSS), and fatal familial insomnia (FFI). Spontaneous and inherited prion diseases are very rare, and affect only about one person per million each year.
In addition to inherited pathogenic mutations in the prion gene, there are also two polymorphisms: methionine (M) or valine (V) at codon 129 (M129V) and glutamine or lysine at codon 219 (E219K). Although these polymorphisms, although not pathogenic in themselves, have a major effect on susceptibility to and expression of prion disease. People who are heterozygous at either of these codons, that is to say have different codons on either copy of the two alleles within the cell, show resistance to sporadic CJD and to acquired prion diseases such as kuru and vCJD.
A very good review article called “Pathogenesis of prion diseases: current status and future outlook” was published recently in Nature Reviews Microbiology (Adriano Aguzzi and Mathias Heikenwalder. Pathogenesis of prion diseases: current status and future outlook. Nature Reviews Microbiology 2006 4: 765-775). In particular, this paper focuses on the role played by the immune system in prion diseases. Well worth a read to update your prion knowledge.
In the first of two papers published in the Journal of General Virology, John Collinge and his colleagues study the effect of the methionine/valine polymorphism at residue 129 (Lewis PA, et al. Codon 129 polymorphism of the human prion protein influences the kinetics of amyloid formation. J Gen Virol. 2006 87: 2443-2449). From studying the structure of the protein, they conclude that the human M/V polymorphism acts by influencing the kinetics of amyloid formation, the underlying biochemical defect which causes the pathogenesis seen in the brains of prion disease victims.
Finally, I’d like to mention a paper which looks at milk from lactating cows that had previously been infected with bovine spongiform encephalopathy (BSE) (Everest, S.J. et al. No abnormal prion protein detected in the milk of cattle infected with the bovine spongiform encephalopathy agent. J Gen Virol 2006 87: 2433-2441). Milk specimens were centrifuged to obtain fractions enriched for cells and these were analysed for disease-associated, abnormal prion protein. The good news is that no abnormal prion protein was identified in the milk of cattle with BSE, at least at their limits of detection.
Despite significant progress in our understanding of prion pathogenesis, there is still much to learn about these diseases, and of course, how to treat them.