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Evolving proteins – no DNA required


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Prions are the infective agents that cause transmissible spongiform encephalopathies such as Mad Cow Disease in humans. All prions affect the brain or neural tissues and are currently untreatable. What makes them particularly fascinating is that unlike other infective agents such as bacteria, protozoa, and viruses, they don’t contain any genetic material. No DNA or RNA. Prions are just misfolded proteins but they are capable of spreading, causing disease, and evolving.

Light photomicrograph of brain tissue (magnified 100X) suffering from vCJD. Image from Public Health Image Library (PHIL) ID#: 10131

Prions spread disease a little like zombies. The prions themselves are misfolded proteins, and when they come into contact with correctly folded versions of the protein they cause them to misfold as well. Once these proteins become misfolded they can go on and convert further proteins to the misfolded form. This misfolded protein accumulates in neural cells and tissues causing damage to the brain. In mammals, all prion diseases are caused by a protein known as PrP (prion protein). The correctly folded form is referred to as PrPC and the misfolded form as PrPSc.

Not only do the prions spread they also change and evolve as they go. There are various different theories as to how a prion, a piece of folded protein with no associated DNA, can evolve. The ‘cloud hypothesis’ is that different variants of PrPSc are present within the organism. Depending on outside environmental pressures, one form may be able to spread quicker or more effectively than others and therefore will be selected for.

The “cloud” hypothesis proposes that prion isolates are intrinsically heterogeneous and consists of major (red) and minor (various colors) PrPSc variants. Changes in the replication environment might provide selective advantages for replication of a minor variant leading to transformation of the PrPSc population. Image from the reference.

A second hypothesis is the ‘deformed template’ model. This puts forward that changes in the environment can themselves cause changes to the prions and generate new PrPSc variants. This expands the pool of PrPSc variants that can be selected for, making it more likely that a successful protein will be able to spread and propagate. It may be that this form of evolution only happens when the environment is not favourable for exact duplication of the misfolded states, so some prions are misfolded slightly differently.

The deformed templating model postulates that diverse structural variants are generated as a result of changes in replication environment. A newly generated variant that fits better than parent PrPSc to the altered environment replaces the original PrPSc variant. image from the reference.

It’s difficult to prove experimentally that the prions are changing due to the environment, and prion research is not my area, but the reference points to some recent research which seems to show prions changing form in response to different environments in hamster brain homogenates. It’s also interesting to consider changes already seen in prions as they cross the species barrier. It could be that as well as providing new evolutionary pressures for more efficient folds, the environment of a new species may change the variety of protein folding.

As well as being exciting for prion researchers, this kind of research raises all sorts of possibilities for the behaviours of proteins in normal situations, inside cells. Prions can evolve as they change proteins around them at a spectacular and alarming rate, but that doesn’t mean that other cellular proteins can’t ‘evolve’ in similar ways, albeit at a slower rate. If the protein in question is one that influences DNA it may be able to stamp its own change into the genetic code, to be passed on to future generations. This may be speculation at the moment, but it opens up a range of exciting possibilities for evolution beyond the genetic.

Reference: Makarava N, Baskakov IV (2013) The Evolution of Transmissible Prions: The Role of Deformed Templating. PLoS Pathog 9(12): e1003759. doi:10.1371/journal.ppat.1003759

S.E. Gould About the Author: A biochemist with a love of microbiology, the Lab Rat enjoys exploring, reading about and writing about bacteria. Having finally managed to tear herself away from university, she now works for a small company in Cambridge where she turns data into manageable words and awesome graphs. Follow on Twitter @labratting.

The views expressed are those of the author and are not necessarily those of Scientific American.





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  1. 1. Uncle.Al 5:21 pm 01/5/2014

    Prions are thermodynamic pathogens. A metastable functional protein conformation is seeded into a lower energy dysfunctional conformation. Metastable molten sodium acetate trihydrate (mp 58 C) or sodium thiosulfate pentahydrate (hypo, mp 45 C) remain liquid at room temperature indefinitely (18 C) until a seed crystal or suitable nucleating event is added. “Tin disease” “tin pest” in European organ pipes.

    There is nothing remarkable about a flood of seeds loosed into a world of variable protein sequences leading to thermodynamic evolution of increasingly stable (and more infective) conformers. Think of it as a proteinaceous “Ice Nine” that gets creative across related chemical compositions.

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  2. 2. S.E. Gould in reply to S.E. Gould 5:38 pm 01/5/2014

    Thanks for the comment. I suppose it depends how you define ‘remarkable’! Prion behaviour can certainly be described through simple thermodynamic rules, but the effect of their behaviour has fascinating and far reaching consequences in a cellular system. Often protein systems and pathways are run on very simple rules (two component feedback systems for example) yet can still be fascinating to study and explore.

    Where prions differ from seeded crystals is that they make exact copies of themselves. Any small changes in form therefore count as mutations and can be selected for, allowing them to evolve.

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  3. 3. SciLawyer 3:37 pm 03/27/2014

    This recently published hypothesis seems relevant: http://www.mdpi.com/2227-7382/2/2/154

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