A scrapie/genetics question

[juliepoudrier]

I'm reading The Family that Couldn't Sleep, by Daniel T. Max. Although the basis for the story is a Venetian family whose members died mysterious insomniac deaths over a couple of centuries, the book is really about prion diseases and the research (and researchers) behind the discoveries of the causes of scrapie, BSE, CJD, and ultimately, the disease killing the family from which the book gained its title: fatal familial insomnia (FFI).

 

There's a quite interesting chapter on scrapie (in which the scrapie outbreak in the UK is blamed largely on extensive inbreeding of sheep in the early 1700s, when Robert Bakewell decided that the best way to improve sheep in the UK was to breed for less bone and more meat), and another on the whole BSE outbreak in the UK. At one point, the author makes these comments:

 

In the early years of this century, working on the assumption that mad cow came from scrapie, Europe set about trying to eliminate the "reservoir" for another BSE outbreak by breeding scrapie-resistant sheep. Since then, unfortunately, researchers have discovered that genotypes that confer resistance to most strains of scrapie actually confer susceptibility to others. [emphasis added] At the same time, French researchers discovered that mad cow somehow crossed into a goat. Prions change their shape and their potency as they jump from one species to another, so no one knows whether the resultant goat-BSE strain will also be dangerous to sheep, cattle, humans, or only to goats.

 

I'm still reading the book (which is a great read for the scientific-minded, by the way), and so haven't gone searching for the primary sources regarding scrapie resistant genes in sheep and resulting increased susceptibility to other strains. I know a lot of folks use gentypes for resistance at specific codons as a selling point for breeding stock, so I was curious whether anyone has any information on what other strains out their such sheep might be more susceptible to.

 

Note that I am not worried about scrapie in my sheep or any sheep I might buy--just curious about the above statement from a scientific curiosity POV. (The book was published in 2006 [Random House], so I imagine there's been some advances in prion research since its publication as well.)

 

J.

[Pearse]

There have been some cases where the animals tested had the ARR/ARR genotype and yet showed deposition of PrP (sc). In most of those cases, the PrP was atypical with extra bands on Western blot.

 

The conclusions in the papers I have seen is that although ARR/ARR confers resistance to most natural ovine TSE's (and BSE), the resistance is not absolute and there may be abnormal prions out there to which normally resistant sheep are not protected completely

 

But, I haven't seen anything that suggests that breeding ARR/ARR sheep makes them more susceptible to other naturally-occurring forms of sheep prion disease.

 

c.f. http://vir.sgmjournals.org/cgi/content/full/85/9/2727

 

For those non-science geeks out there, ARR refers to three amino acids in the normal sheep prion protein (PrP). These are amino acids 171, 154, and 136 in the chain of amino acids that make up the PrP protein. If the amino acid Alanine (A) is present at codon 136, the sheep is more resistant. If Valine (V) is there, more susceptible. Codon 171, if Glutamine (Q) or Histidine (H) is there the animal is susceptible. Arginine ® confers resistance.

 

So ARR/ARR sheep are resistant, and VRQ/VRQ sheep are susceptible. Why?

 

amino acids are three dimensional and are different sizes. They also have different charges. Some are water repellent (hydrophobic) and some attract water (hydrophilic). Proteins start out as a long chain but the chain folds up almost immediately it is formed, into a 3 dimensional shape, determined to a large extent by the differences in the amino acids.

 

An ARR protein has a different shape than a VRQ protein. Why is that relevant?

 

Scrapie occurs when a mutant form (read misfolded) of the normal PrP protein meets up with a normal form. The mutant form interacts with the normal form and twists it into a mutant form (making many more copies). Two things happen. The mutant forms of PrP form clumps which interfere with how the cell works. They also can't be broken down (most proteins in cells are chopped up fairly quickly as new ones are made). There's also some evidence that the mutant forms expose parts of the protein normally folded inside and that some of these bits are toxic to nerve cells.

 

The ARR protein is "stiffer". It can't be forced into the mutant shape by mutant prions.

 

For any budding computer scientists or biochemists out there, decoding the rules by which proteins fold is the next holy grail of science as significant an achievement as some of the big questions in particle physics so get cracking.

[Mark Billadeau]

More reading with the same info:

 

Pruritus is a common feature in sheep infected with the BSE agent

 

Forty-seven (34%) of 139 sheep, which comprised 123 challenged sheep and 16 undosed controls, were positive for BSE. Affected sheep belonged to five different breeds and three different genotypes (ARQ/ARQ, VRQ/VRQ and AHQ/AHQ). None of the controls or BSE exposed sheep with ARR alleles were positive.

 

TSEs are not neccessarily species specific (in terms of "infection").

Sheep can be "infected" with BSE & scrapies.

ARR sheep did not become "infected" with BSE.

 

Mark

[juliepoudrier]

Thanks Pearse and Mark. I have to say that the whole political thing behind TSEs in the US (and elsewhere) can be kind of scary.

 

J.