Mad fish disease

10 March 2009
Posted by Chris Smith.

 BSE, so-called "mad cow disease" and its human equivalent Creutzfeld-Jakob disease, or CJD, are rare but serious degenerative brain diseases. We've known for over twenty years that they are caused by a rogue protein, known as the prion protein or PrP.  PrP exists in two different forms, or shapes, in the brain.

Human prion protein, residues 125-228, created from protein database (PDB) entry 1QM3.The healthy, normal-shaped protein plays a useful role in the brain, but the rogue form spreads rapidly through the brain, causing healthy proteins to adopt the abnormal shape and causing disease. But it's not clear why we produce PrP in the first place, or what its exact function is in the body. Now new results from German researchers shed new light on the role of normal PrP, which could explain more about the causes of prion diseases, and even lead to new treatments.

It's been a tough problem to crack, mainly because experiments with genetically-modified mice lacking the prion protein have shown them to be perfectly healthy, so it's been difficult to pin down a purpose for it.

Writing in this week's edition of PloS Biology, Edward Malaga-Trillo and his colleagues studied developing zebra fish to look at the role of the prion protein in embryonic development. Zebra fish are a handy model for these kinds of studies because not only are they quick to grow, they are also transparent and easy to study during embryonic development, so you can see processes going on in the living fish quite easily.

The scientists injected zebra fish eggs with chemicals called morpholinos - these are a bit like DNA, and they block the production of specific proteins. In this case, they used morpholinos that were specifically designed to target the prion protein.  They found that the zebrafish were unable to develop properly - for example, they didn't develop a proper nervous system - and they died.

The researchers showed that other proteins normally found at sites of contact between cells had disappeared, so the cells weren't able to communicate properly. So it looks like the prion protein is playing an important role in organising these cell to cell contacts, acting a bit like "glue" and helping to establish and maintain the contacts. The prion protein probably also has the same role in mice or humans, but because we're more complicated than fish, it hasn't been possible to tease it out.

This won't lead to a cure right now, but it's an important piece in the jigsaw. If we can understand shat the prion protein normally does, we'll have more of an idea how it goes wrong in CJD. And - as we discussed a couple of weeks ago - the prion protein may play a role in Alzheimer's disease, so this is an important advance for that avenue of research too.

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