Prions

The standard model of pathogens (agents that cause disease) that you will have been taught is that there are three main types of pathogen: viruses, bacteria and fungi. Even when we include Protoctista like plasmodium (the organism that causes malaria) and the delightful parasitic worms there is still one remaining. It is the prion, a misfolded protein. Whilst they are barely relevant to medicine they have the potential to shatter long held scientific beliefs about disease.

 Prion diseases are exceedingly rare. The three prion diseases affecting humans I could find are Kuru, a disease confined to the Fore people of New Guinea who eat the brain of their dead relatives out of respect and Creutzfeldt-Jakob disease, a human form of mad cow disease, and the amazingly titled Gerstmann–Sträussler–Scheinker syndrome, an extremely rare hereditary condition. Animal prion diseases are a little more common, mad cow disease and Scrapie are the most relevant.

Members of the Fore tribe that have not suffered from kuru apparently due to a
genetic mutation offering increased resistance

 All prion diseases are incurable and inevitably fatal and all work in roughly the same way. Infection begins with a prion, a misfolded protein entering or being accidentally made in the body. Somehow the prion propagates by transferring its misfolded state to a similar but normally folded proteins. This causes an exponential growth in the number of prions. Death usually occurs not by the lack of the normal protein but by the prions accumulating in the brain and spinal cord. There they damage neurones and form cavities. For this reason prion diseases are also called Transmissible Spongiform Encephalopathies (transmissible because it can be passed on through contaminated blood or tissue, spongiform because of the sponge-like result on the brain and encephalopathies refers to diseases of the brain). The first symptoms of this condition are usually personality changes, depression and loss of movement control and an unsteady gait. Insomnia has also been reported. These develop into extreme dementia and death.

the result of  spongiform encephlopathies

 The existence of prions has had an impact on the treatment of surgical apparatus. All surgical tools are decontaminated before re-use but ones used on the brain now especially so. Prions appear to be able to survive normal protease, heat and radiation treatments. Only extremely high temperature or an extreme pH guarantee that something is prion free.

 The discovery of prion diseases caused such controversy because it appears to go against the “central dogma of molecular biology” which puts nucleic acids as the basic unit of information. Prions appear to replicate without any sort of nucleic acid to code for the protein. This seems to defy normal biology. Where does the information of the order of amino acids come from if not from DNA or RNA? We still aren’t quite sure how prions are able to replicate. Several hypotheses have been made but all are a bit vague.

 The protein only hypothesis is the idea that no nucleic acids are involved and that prions replicate from proteins by some form of self-catalysis (it catalyses a reaction which forms it as a product). Supporting this hypothesis is the observation that animals lacking a protein that can become protease resistant aren’t affected by prion diseases. Presumably this type of protein is reactant in the prion replication.

How is it done?

 Other hypotheses place the misshapen prion proteins as a side effect not a cause of Transmissible Spongiform Encephalopathies. One hypothesis denies the lack of nucleic acids and attributes the diseases to a slow-acting virus. Supporting the idea are the subtle changes in pathology in prion diseases (different strains perhaps) and the finding of virus like particle in a small number of scrapie-infected animals. Another hypothesis, a masterpiece of lateral thinking, attributes the disease to a complicated form of manganese poisoning.¹ the idea is supported by evidence that manganese can turn normal proteins into protease resistant polymers and brain diseases do seem to be prevalent around areas of manganese mining. None of the hypotheses explain all of the evidence and prions remain an unexplained mystery in the side of the otherwise stable science of pathogenesis.

1-Prion protein polymerisation triggered by manganese-generated prion protein seeds.

http://www.ncbi.nlm.nih.gov/pubmed/22007749