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.”

[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