Tag Archives: prions

Slowing the progress of prion diseases

At present, the jury is still out on how prion diseases affect the body let alone how to cure them. We don’t know if amyloid plaques cause neurodegeneration or if they’re the result of it. Due to highly variable glycophosphatidylinositol (GPI) anchors, we don’t know the structure of prions. Due to their incredible resistance to proteolysis, we don’t know a simple way to destroy prions even using in an autoclave. The current recommendation[0] by the World Health Organisation includes the not so subtle: “Immerse in a pan containing 1N sodium hydroxide and heat in a gravity displacement autoclave at 121°C”.

There are several species including Water Buffalo, Horses and Dogs which are immune to prion diseases. Until relatively recently it was thought that rabbits were immune too. “Despite rabbits no longer being able to be classified as resistant to TSEs, an outbreak of ‘mad rabbit disease’ is unlikely”.[1] That being said, other than the addition of some salt bridges and additional H-bonds, we don’t know if that’s why some animals are immune.

We do know at least two species of lichen (P. sulcata and L. plumonaria) have not only discovered a way to naturally break down prions, but they’ve evolved two completely independent pathways to do so. How they accomplish this? We’re still not sure in fact, it was only last year that it was discovered that lichens may be composed of three symbiotic partnerships and not two as previously thought.[3]

With all this uncertainty, one thing is known: PrPSc, the pathogenic form of the Prion converts PrPC, the cellular form. Just preventing the production of PrPC may not be a good idea, mainly because we don’t know what it’s there for in the first place. Previous studies using PrP-knockout have shown hints that:

  • Hematopoietic stem cells express PrP on their cell membrane. PrP-null stem cells exhibit increased sensitivity to cell depletion. [4]
  • In mice, cleavage of PrP proteins in peripheral nerves causes the activation of myelin repair in Schwann Cells. Lack of PrP proteins caused demyelination in those cells. [5]
  • Mice lacking genes for PrP show altered long-term potentiation in the hippocampus. [6]
  • Prions have been indicated to play an important role in cell-cell adhesion and intracellular signalling.[7]

However, an alternative approach which bypasses most of the unknowns above is if it were possible to make off with the substrate which PrPSc uses, the progress of the disease might be slowed. A study by R Diaz-Espinoza et al. was able to show that by infecting animals with a self-replicating non-pathogenic prion disease it was possible to slow the fatal 263K scrapie agent. From their paper [8], “results show that a prophylactic inoculation of prion-infected animals with an anti-prion delays the onset of the disease and in some animals completely prevents the development of clinical symptoms and brain damage.”

[0] https://www.cdc.gov/prions/cjd/infection-control.html
[1] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3323982/
[2] https://blogs.scientificamerican.com/artful-amoeba/httpblogsscientificamericancomartful-amoeba20110725lichens-vs-the-almighty-prion/
[3] http://science.sciencemag.org/content/353/6298/488
[4] “Prion protein is expressed on long-term repopulating hematopoietic stem cells and is important for their self-renewal”. PNAS. 103 (7): 2184–9. doi:10.1073/pnas.0510577103
[5] Abbott A (2010-01-24). “Healthy prions protect nerves”. Nature. doi:10.1038/news.2010.29
[6] Maglio LE, Perez MF, Martins VR, Brentani RR, Ramirez OA (Nov 2004). “Hippocampal synaptic plasticity in mice devoid of cellular prion protein”. Brain Research. Molecular Brain Research. 131 (1-2): 58–64. doi:10.1016/j.molbrainres.2004.08.004
[7] Málaga-Trillo E, Solis GP, et al. (Mar 2009). Weissmann C, ed. “Regulation of embryonic cell adhesion by the prion protein”. PLoS Biology. 7 (3): e55. doi:10.1371/journal.pbio.1000055
[8] http://www.nature.com/mp/journal/vaop/ncurrent/full/mp201784a.html

Prions

The most recent paper presented to the OPIG journal club from PLOS Pathogens, The Structural Architecture of an Infectious Mammalian Prion Using Electron Cryomicroscopy. But prior to that, I presented a bit of a background to prions in general.

In the 1960s, work was being undertaken by Tikvah Alper and John Stanley Griffith on the nature of a transmissible infection which caused scrapie in sheep. They were interested in how studies of the infection showed it was somehow resistant to ionizing radiation. Infectious elements such as bacteria or viruses were normally destroyed by radiation with the amount of radiation required having a relationship with the size of the infectious particle. However, the infection caused by the scrapie agent appeared to be too small to be caused by even a virus.

In 1982, Stanley Prusiner had successfully purified the infectious agent, discovering that it consisted of a protein. “Because the novel properties of the scrapie agent distinguish it from viruses, plasmids, and viroids, a new term “prion” was proposed to denote a small proteinaceous infectious particle which is resistant to inactivation by most procedures that modify nucleic acids.”
Prusiner’s discovery led to him being awarded the Nobel Prize in 1997.

Whilst there are many different forms of infection, such as parasites, bacteria, fungi and viruses, all of these have a genome. Prions on the other hand are just proteins. Coming in two forms, the naturally occurring cellular (PrPC) and the infectious form PrPSC (Sc referring to scrapie), through an as yet unknown mechanism, PrPSC prions are able to reproduce by forcing beneign PrPC forms into the wrong conformation.  It’s believed that through this conformational change, the following diseases are caused.

  • Bovine Spongiform encephalopathy (mad cow disease)
  • Scrapie in:
    • Sheep
    • Goats
  • Chronic wasting disease in:
    • Deer
    • Elk
    • Moose
    • Reindeer
  • Ostrich spongiform encephalopathy
  • Transmissible mink encephalopathy
  • Feline spongiform  encephalopathy
  • Exotic ungulate encephalopathy
    • Nyala
    • Oryx
    • Greater Kudu
  • Creutzfeldt-Jakob disease in humans

 

 

 

 

 

 

 

 

Whilst it’s commonly accepted that prions are the cause of the above diseases there’s still debate whether the fibrils which are formed when prions misfold are the cause of the disease or caused by it. Due to the nature of prions, attempting to cure these diseases proves extremely difficult. PrPSC is extremely stable and resistant to denaturation by most chemical and physical agents. “Prions have been shown to retain infectivity even following incineration or after being subjected to high autoclave temperatures“. It is thought that chronic wasting disease is normally transmitted through the saliva and faeces of infected animals, however it has been proposed that grass plants bind, retain, uptake, and transport infectious prions, persisting in the environment and causing animals consuming the plants to become infected.

It’s not all doom and gloom however, lichens may long have had a way to degrade prion fibrils. Not just a way, but because it’s apparently no big thing to them, have done so twice. Tests on three different lichens species: Lobaria pulmonaria, Cladonia rangiferina and Parmelia sulcata, indicated at least two logs of reduction, including reduction “following exposure to freshly-collected P. sulcata or an aqueous extract of the lichen”. This has the potential to inactivate the infectious particles persisting in the landscape or be a source for agents to degrade prions.