[thedoc (OP)]

Sara asked the Naked Scientists:
   
I have a question I am hoping you can help me with. It is in regards to familial cjd and I couldn't find the answer in the other topics.

I know there are normal PRPc throughout the body in non-neural tissues. I also know, genetic mutations in the DNA instructions can cause the PRPC to change from normal PRPC to abnormal PRPSc, then it snowballs from there.

My question is, when the genetic mutation gives instructions for the PRPC to change to abnormal PRPSC, does that happen only in the brain/CNS?..... Or do the other normal PRPC cells in non- neural tissues change to the PRPSC as well?

I wasn't sure if all the PRPC cells throughout the body changed, due to the genetic mutation, or just the neural tissues?

I am asking this question in regards to tissue transplants. I was curious if a tissue donor had the familial cjd genetic mutation ( that was not expressed yet), and donated tissue... would the normal PRPC in that non-neural tissue switch to PRPSC later on when the genetic change occurs.... Therefore making the donor non-neural tissue infectious and causing CJD in the recipient?

I cannot find this info anywhere! Hoping you can help! Thanks!

Sara

What do you think?

[evan_au]

The first thing to say is that CJD is very rare in the general population, producing detectable symptoms in about 1 person per 1 million population, in a given year. It mostly affects people aged 60 years or above.

As I understand it...

• The major Protein found in Prions (PRP) comes in two different shapes, the normal water-soluble PrP^C, and the disease-causing PrP^Sc which builds up insoluble protein aggregates which cannot be broken down by the body.
  
• The PrP^Sc clumps build up to such an extent that it kills the surrounding cells
  
• Contact with PrP^Sc can turn the normal PrP^C into the dangerous PrP^Sc
  
• Once PrP^Sc appears in the body, it grows exponentially
  
• Some people have mutations in the gene for PrP (familial Creutzfeldt Jakob disease, CJD), which means that their PrP^C is more likely to turn into PrP^Sc, either spontaneously, or by exposure to an external trigger such as eating brain/nervous system tissue from cows with BSE.
  
• Transplantation of tissue with existing CJD would count as an external trigger
  
• PrP is expressed in many tissues throughout the body, the major ones being the brain, spinal cord and nasal bulb, but also in the lungs, kidney, liver and other organs to a much lesser extent. (See the horizontal axis to identify the tissue relevant to this case.)
  
• Researchers have found that PrP^Sc could be detected in the blood of animals long before the symptoms appeared. This justifies the bans on blood donations and transplants from people with a family history of CJD.
  
• So it appears that once it develops, PrP^Sc will spread around the body throughout all tissues expressing this protein, producing multiple small lesions in all these tissues (a biopsy of the tonsils is often used for diagnosis, because the tonsils are readily accessible). In the brain, these small lesions eventually grow and merge to appear sponge-like.
  
• However, it will grow most explosively in tissues which have the highest concentrations of PrP, ie nerve tissue like the brain and spinal cord. It is usually the neurological symptoms which are detected first

For the case of transplantation from someone with familial CJD:

• Yes, that transplanted tissue is more likely to produce some misfolded PrP^Sc at some time. Doctors could estimate this period.
  
• As this was non-neural tissue, the chance of expressing PrP^Sc is much lower than in nervous tissue; for example, the kidney expresses PrP about 7 times less than the brain, and Liver about 80 times less than the brain.
  
• Whether it goes on to cause CJD in the tissue recipient depends on the genetics of the recipient - some genetic variants seem more resistant to PrP^Sc than others.
• Some researchers believe that the incubation period of the disease in the bulk of the population may exceed 50 years - but there isn't enough data to evaluate this due to the uncertainties in exposure levels and date of exposure.

Unfortunately, from this I would guess that this transplant has increased risk of developing CJD in this recipient, compared to the very low risk in the general population.

• However, you would need to talk to a relevant expert (not a discussion board!) about the extent of risks, what is the likely age of onset, and whether other conditions are likely to prove fatal to this individual before then.
  
• There are new, more sensitive blood tests in research labs that could monitor the condition - here there is a known exposure at a known date, and this could be a valuable input to research, potentially impacting the lives of many people.

Presumably, the transplant has already been a life-saver, and this must be weighed up against the attendant risks of having another transplant from a different donor.

[chris]

I also put this question to Cambridge virologist Stacey Efstathiou, who has an interest in prion diseases. He said:

"The CNS has the highest levels of PrP expression so the probability of a stochastic change in structure is highest at this site. This probably explains why sporadic CJD results in PrPSC accumulation in the CNS rather than lymphnodes. There is no evidence that sporadic cjd is transmitted by blood transfusion and at post mortem PrP sc is not detected in lymphnodes. The situation is very different in the case of BSE....injestion leads to PrP accumulation in lymphnodes before changes are observed in CNS. This must mean that PrP expression occurs in the lymphoreticular system and is efficiently converted to an abnormal form by vCJD...vCJD is therefore different and has the potential for transmission via blood transfusion."


I followed this up by asking:

"So why do you think that sporadic CJD doesn't seed the periphery, using as an exit route from the CNS the same pathway that allows BSE to get in following oral challenge (spleen, sympathetic nerves etc) and hence amplify systemically?

And, when an animal is challenged exclusively intracerebrally with BSE, is there any evidence of subsequent peripheral amplification (in LNs or spleen), or does the agent remain confined to the CNS?"

To which Stacey replied:

"I think we can assume that BSE is a bit special i.e. it very efficiently converts PrPs from different species and is probably just more efficient at conversion -hence its ability to amplify in lymph nodes. I'm not sure anyone has looked at the LN's or spleen of animals injected i.c with BSE-I would predict that you world see spread to lymphoid organs."

I hope that helps.

Chris

[evan_au]

From the graphic at http://en.wikipedia.org/wiki/File:PBB_GE_PRNP_215707_s_at_tn.png

• It appears that PrP is expressed at a similar rate in lymph nodes as in tonsils (both play a role in the immune system; right-hand side of the graphic). These could certainly amplify PrP^Sc and spread it around the body.
  
• Some types of white cells express PrP to an even greater extent than the lymph nodes as a whole (light blue bars, left-hand side)
• The Bronchial Epithelial cells (in the lungs) express PrP to an even greater extent than the lymph nodes
• These other tissues have an ability to grow new cells to work around damage; new cell growth in the adult CNS (Central Nervous System = brain+spinal cord) is more limited, so the disease would progress further, faster and more destructively in the CNS.

[Sdm52980]

Thank you all for the information. I do have one question. Is cjd present in transmissible levels outside of the CNS? I know it has been found in periphreal tissues, but are the levels high enough to be transmissible?  Here is a little history...I had an eye issue and needed an amniotic membrane graft from a donor placenta. If the do or was incubating cjd could the placenta also have cjd? Would it be transmissible? Can't seem to find much on this. It has really taken a toll on me and I wish I would have never received the graft!!! Thanks!!