Its disease Jim, but not as we know it…..

Bacteria, viruses and other assorted microscopic lurgies, as I’m sure the good folks at Dettol have made you aware, are absolutely everywhere.  With increasing health awareness people feel the need to protect themselves from the teeming hordes, and yet a large majority are not dangerous at all, in fact they’re quite happy living right there….On your face.

In fact, scientists even know a great deal about the ones that can actually pose a threat, allowing us to make vaccinations and antibiotics (or at least we used to, but that’s a blog for another day).  What I actually want to introduce to you today is a fascinating little nasty called Prion Protein (PrP) that we know very little about. Remember that whole BSE “mad cow disease” crisis?  That was a mutated form of PrP, a small naturally occurring protein found in almost all tissues of the human (and cow) body that caused the execution of over 280,000 cows, costing the EU around £3bn cumulatively.

But First, A little History:

First observed in humans in the 20th century among tribes of the southern fore in Papua New Guinea, mutated prion (PrPSc) spread among indigenous tribes as a result on ritualistic cannibalism of the cerebral tissue upon death! Eating the diseased brain from only one sufferer resulted in this becoming the major cause of death among these tribes. This highlights perhaps the defining characteristic of prion diseases, their transmissible nature. Despite the protein being endogenous to one individual, it was able to adapt and mediate toxicity in other people without being recognised by the immune system.  Therefore prion protein is responsible for a group if diseases known as Transmissible Spongiform Encephalopathies (TSE), so named for the accumulation of intracellular vesicles during neuronal degeneration, giving brain tissue a “spongy” appearance.  This group of diseases are invariably fatal, incurable and to date we can’t even agree on how it mediates its neurotoxicity.

So why is it fascinating?

(Figure 1:  ribbon diagram of two normal, non-pathogenic PrP molecules)  Taken from: Lee et al,. 2010

(Figure 1: ribbon diagram of two normal, non-pathogenic PrP molecules)
Taken from: Lee et al,. 2010

For me this is precisely what is so curious about PrP. Consider a normal disease causing bacteria, a hugely complex multi-molecular organism containing a genome and which is capable of metabolising food, excreting and mating, things we all have in common (even with salmonella). Prion protein however is not living, in fact it is largely accepted that it contains no genetic material (nucleic acids) of any kind, and is therefore even more primitive than some viruses that at least have an RNA genome.

Somehow without this PrPSc still mediates infection and transmission from cell to cell and can control is own replication, using nothing other than its structural conformation.

So what do we know so far?

Currently there are 3 major hypotheses surrounding what actually constitutes this mysterious particle, the most widely accepted and original being the “protein only” hypothesis by J.S Griffith in 1967, this states that the infectious particle (PrPSc) is devoid of nucleic acid and is identical to a post-translationally modified form of the original wild type protein (PrPC). This was observed when the infectivity of brain extracts injected into mice was retained after treatment with UV, high temperature and pressure, things that would destroy DNA and kill viral or bacterial particles.

(figure 2: aggregate of multiple PrPSc variants containing largely beta sheet structure)  Taken from: Wasmer et al,. 2008

(figure 2: aggregate of multiple PrPSc variants containing largely beta sheet structure)
Taken from: Wasmer et al,. 2008

We can also postulate a mechanism of how PrPC becomes toxic PrPSc in the cell. Under normal conditions the protein adopts a helical structure containing only 2 beta sheets shown in figure 1 (the pink one), the PrPSc infectious particle has a different conformation that enables it to bind to wild type PrPC and induce it to change shape into the pathogenic form (PrPSc), termed the “template directed folding model of prion conversion”.   This autocatalytic and self-replicative process leads to formation of aggregates in the brain containing largely beta sheet structure that prevents protein degradation, induces stress in the endoplasmic reticulum and ultimately result in neural atrophy.

Interestingly prion protein has recently been implicated as a receptor of amyloid, a major determinant on Alzheimer’s disease and may contribute to the characteristic plaque formation that causes neurodegeneration is this disease, although this remains to be fully tested.

Ironically, despite knowing little about it, there is far too much information and hearsay to give any solid detail in this short blog, so I’ll leave you with this:

TSE’s are the only known disease caused by a self-inducing protein to date and the potential for cross-species prion diseases poses a sizable threat to human health, yet further study aims to answer the questions:  How does it mediate neurotoxicity? How does the conformation of prion protein enable it to self-replicate, and rather alarmingly – what does normal prion protein even do?


Some interesting reviews and image sources are listed below:

Aguzzi A, Nuvolone M, & Zhu C (2013). The immunobiology of prion diseases. Nature reviews. Immunology, 13 (12), 888-902 PMID: 24189576

Acquatella-Tran Van Ba I, Imberdis T, & Perrier V (2013). From Prion Diseases to Prion-Like Propagation Mechanisms of Neurodegenerative Diseases. International journal of cell biology, 2013 PMID: 24222767

Lee S, Antony L, Hartmann R, Knaus KJ, Surewicz K, Surewicz WK, & Yee VC (2010). Conformational diversity in prion protein variants influences intermolecular beta-sheet formation. The EMBO journal, 29 (1), 251-62 PMID: 19927125

Wasmer C, Lange A, Van Melckebeke H, Siemer AB, Riek R, & Meier BH (2008). Amyloid fibrils of the HET-s(218-289) prion form a beta solenoid with a triangular hydrophobic core. Science (New York, N.Y.), 319 (5869), 1523-6 PMID: 18339938


2 responses to “Its disease Jim, but not as we know it…..

  1. To say that PrPsc is mutated is not correct. That implies a genetic abnormality while only a conformational change is postulated.

    Stanley Prusiner published a piece in Science in which he proposed prion-like activity as a unifying concept for many central nervous system diseases involving abnormal protein deposition. The reference is Cell biology. A unifying role for prions in neurodegenerative diseases. The reference is:

    Prusiner SB.
    Science. 2012 Jun 22;336(6088):1511-3. doi: 10.1126/science.1222951

  2. While this may be correct, there are definite classified mutations within the prion protein that increase the predisposition towards the pathogenic beta sheet structure and confer resistance to Proteinase K degradation in both the C-terminal region and hydrophobic core of the protein respectively.
    Plus its simpler to state a “mutant” form than attempt to cover all possible contributions to pathology in these little blogs 🙂

    You are however our first ever comment – congratulations and thank you

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