Key to understanding and treating TSEs is the identification of the cause(s) of the various strains of the condition.

This knowledge enables:

• distinction between genetic vs. external cause
  • genetic causes cannot be easily prevented since the defect is automatically passed from one generation to the next
    • in animal models, if a genetic link is established, a screening system can aide in eliminating animals from the breeding pool
    • in humans, each genetic defect has a different pattern of clinical expression that may require various treatment regimes
• possible elimination of the condition if the TSE can be identified as spreading from an external agent
  • kuru has been controlled since the cause (cannabalism) was identified and the practice discouraged
  • the cause of BSE is now known (ruminant to ruminant feeding) and the disease is being eliminated

   

Identifying the Specific Genetic Cause of Familial (Inherited) TSE's such as vCJD, BSE, Scapie

• At some point, a random DNA mutation(s) occurred that resulted in a TSE-developing subject (see figure below)
• The affected subject and a healthy control are identified
• DNA (or cDNA) is prepared from both the subject and control
• The sequence of the PrP DNA is determined for both the subject and control
• Sequence differences are identified between the subject and control
• Relatives of the patient may be tested to determine genetic linkage and expression pattern (dominant or recessive)
• Offspring of the subject may inherit the DNA mutation, whereas offspring of the control are healthy
  • note that offspring may inherit TSE DNA, in the figure below TSE or Normal Progeny can arise from a TSE parent
  • this is not a result of DNA 'healing' or repair
  • since we all have 2 copies of every gene, most likely a TSE mutation would only be found in one of the DNA copies
  • hence half of the progeny from TSE individuals will inherit TSE DNA and half will inherit Normal DNA
  • TSE or Normal DNA can come from either parent although the illustration indicates TSE DNA coming from the sire

Identifying the Cause of non-Familial TSE's

• At some point, a random DNA mutation(s) occurred that resulted in a TSE-developing subject
• The mutation can be identified in the original 'founder' animal as described for Familial TSEs

However, with non-familial TSEs conclusive identification of the cause of the TSE in subsequent infections in impossible

• DNA of the founder and control make TSE and normal mRNA, respectively
• mRNA of the founder and control make mutated mis-folded TSE PrP^Sc and normal PrP protein, respectively

• Instead of being inherited, non-familial TSE is transmitted by the PrP^Sc protein, not by genetic material (DNA)

• TSE is spread by cannabalism (kuru), ruminant to ruminant feeding (BSE) or close animal contact (scrapie)
• Only the founder animal that began the disease has the genetic defect that encoded mutant PrP^Sc
• Subsequently infected animals have non-mutated mis-folded PrP (i.e. PrP^Sc) and normal DNA and mRNA
• Thus, the mutation that originated the disease is lost and cannot be directly identified by studying sick animals

 

Strain Typing

• At this point lesion comparisons must be made using a common carrier
• Mice and often Syrian hampsters are injected with brain extracts (or extracts of other tissues) from infected animals

 

• After the appropriated incubation period the mice brains are examined
• Strains of TSE have unique effects on the brain (neurologic fingerprint) and the characteristics may be maintained when passaged to another animal
  • as shown in the figure above the cattle was identified as have a TSE similar or identical to the middle sheep
• TSE's sharing a common origin can be identified this way as the infected mice will share common pathological effects on brain structure
  • this is the means that was used to identify the likely cause of vCJD as being BSE
• by this means it is also possible to determine if BSE arose from scrapie
  • to date scrapie and BSE have unique effects on mouse pathology and no link has been established
• by this means it may be possible to determine if sheep have contracted or eventually develop BSE
  • this latter possibility could lead to transmission of a TSE from 'BSE-scrapie' sheep; but no such link has been established

However, it should be noted that the fidelity of the neurologic fingerprint depends highly on the new host

• in the figure above the neurologic fingerprinting may appear to be loss when passaged through an intermediate species (sheep to cattle to the pink mouse, in this example)
• however, the new test host must be isogenic as the clinical and neurological expression of TSE depend on the host genetics, in the above example two different strains of mice were used to fingerprint the bovine TSE and gave differing results
• identifing the type of TSE was possible using the isogenic mice (light grey mice in the figure)
• accurate fingerprinting and identification of TSE strains must be performed and compared using isogenic test 'host' animals (as in the left two examples in the above figure)
• click on image to learn more about strain fidelity