Prions: mysterious shape shifters

Everywhere and nowhere

It is the strangest thing to see a vibrant and healthy Colorado bred elk begin to shrivel and waste away before your eyes. It is even more frustrating to feel that old familiar tinge of complete helplessness when the realization comes to you that chronic wasting disease has taken (CWD) hold of another victim. No matter how aggressive and careful you are there is literally nothing that can be done once this mysterious disease takes hold.

Thankfully, the incidence of this prion based sickness is relatively rare and slow to ravage whole herds. This is good as the best we can do to control CWD is to monitor it by testing the tissues of captive adult animals that have died or researching “test and cull” methods for eradicating it from wild herds.

The mechanisms that make this disease so bizarre and counter intuitive starts with the causative agent – a prion- a small protein structure without any nucleic acid. They are described as “small proteinaceous infectious particles which resist inactivation by procedures that modify nucleic acids.”

This is indeed beyond strange. The idea that a protein structure by itself can cause disease defied a lot of what was known about infectious disease. The infected animals are usually neurological and the disease is now classified into a family of “spongiform encephalopathies” based on the post mortem lesions found in affected mammals¹- of which most seem to have some version of this thing (table 1). They are all characterized by varying degrees of loss of motor control, dementia, wasting (paralysis) and eventually death.

Table 1 some prion diseases:

• Scrapie: sheep
• TME (transmissible mink encephalopathy): mink
• CWD (chronic wasting disease): muledeer, elk
• BSE (bovine spongiform encephalopathy): cows
• CJD: Creutzfeld-Jacob Disease: human
• GSS: Gerstmann-Straussler-Scheinker syndrome: human
• FFI: Fatal familial Insomnia: human
• Kuru : human
• Alpers Syndrome: human

An interesting historical anecdote regarding early prion research is touched on by Dr Shaun Heaphy lecturer at the University of Leicester “Kuru is the condition which first brought prion diseases to prominence in the 1950s. Found in geographically isolated tribes in the Fore highlands of New Guinea. Established that ingesting brain tissue of dead relatives for religious reasons was likely to be the route of transmission. They ground up the brain into a pale grey soup, heated it and ate it. Clinically, the disease resembles CJD. Other tribes in the vicinity with same religious habit did not develop the disease. It is speculated that at some point in the past a tribe member developed CJD, and as brain tissue is highly infectious this allowed the disease to spread. Afflicted tribes were encouraged not to ingest brain tissue and the incidence of disease rapidly declined and is now almost unknown.” This rather macabre custom did illustrate how this strange infection behaved and how it might work through a population of people.

Even more intriguing, these prions seem to be related to a normal and abundant cellular protein (PrPc) located on the membrane on run of the mill neural cells. These prion like structures have a different structural shape than infectious prions and are perhaps functionally linked with normal neural transmission, though no one really knows for sure.

Prions and these PrPc proteins seem to have species specific structures but these configurations are fairly similar across the board. This species specificity dramatically slows down cross species infections and makes such jumps far less probable, but not impossible- especially if there is a susceptible individual on the other end.

The prion varies in its structural three dimensional forms from the normal PrPc protein and it’s this structural difference that seems to make them so insidiously pathological. To make matters worse, it seems there may be genetically susceptible individuals that are more prone to having their own PrPc proteins “shape shift” into the pathological infectious prion by coming into contact with a prion (by the way, not all shape shifted prions are lethal).

Interestingly, that it is possible to eventually “transform” an infectious prion from one species to another susceptible species is a prime example of witnessing evolution “unplugged” right before our eyes. The ability of these prions to evolve structurally and in time come up with the right configuration to cross species without any genetic elements is remarkable.

As ERV puts it “How does something with the same amino acid sequence evolve??”. With respect to prion research being done by Dr Bartz she adds “The idea I pitched to Dr. Bartz (the idea he was already planning on pitching to the scientific community hehe, I iz smrt) is that prions operate like HIV-1. But instead of exploring sequence space like my HIV, his prions explore structure space. One protein exploring all possible structural configurations. It has an optimal configuration for minks, but needs to explore and find a more optimal configuration for ferrets.” Amazing stuff!

What does a normal PrPc do? What makes its shapeshifted version so lethal? According to the Prion Institute “Studying how and why proteins misfold and the genetics, diagnoses and treatments of prion diseases will have positive implications for both animal and human health issues.”

Indeed, the possible breakthroughs for understanding the prion phenomenon may have staggering implications towards not just understanding the spongiform encephalopathies, but other degenerative neural diseases (i.e.; Alzheimer) as well as shed light on normal brain physiology. All this from a tiny inert blob of protein- reality is indeed far stranger than fiction.

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1) Visible end results at post-mortem are non-inflammatory lesions, vacuoles, amyloid protein deposits and astrogliosis.