PrP^Res in TSE Urine

The first report of a protease resistant form of PrP in the urine of animals and humans affected with TSE is quite notable.

PrP^Res was found in the urine of:

• hamsters inoculated with Scrapie
  • as early as 17d post inoculation (long before clinical and pathological changes)
    • (however, not between 35 and 49d post inoculation)
    • these findings may indicate clearance of inoculated PrP^{Sc at day 17}
  • in increasing amount from 56d post inoculation until clinical signs appeared (day 105)
• cattle with BSE
• humans with CJD
  • E200K mutation

PrP^Res was not found in the urine of:

• normal hamsters
• normal cattle
• normal humans

The protein found in urine was entitled UPrP^Sc by the authors.

UPrP^Sc appears to differ from brain-derived PrP^Sc.

• When UPrP^{Sc 27-30 (from sedemented, dialysed} and proteinase K digested urine) was inoculated
  • hamsters did not develop clinical symptoms even after 270 d
  • hamsters did have UPrP^Sc in their urine
    • thus the UPrP^{Sc 27-30 was transmitted and replicated within the new hosts}
• When brain-derived PrP^Sc (diluted non-digested brain) was inoculated
  • hamsters elicited clinical symptoms after 80d
  • hamsters had UPrP^Sc in their urine
    • thus the brain-derived PrP^{Sc was transmitted, replicated and pathogenic within the new hosts}

Thus UPrP^Sc 27-30 may:

• result in subclinical tranmission; i.e. animals that are 'carriers' only
  • whether, these 'carriers' can tranmit the disease has yet to be determined.
• have a considerably delayed onset of clinical signs versus brain-derived PrP^Sc
  • whether this is due to differences in the intrinsic transmissibility of urinary or brain-derived PrP^Sc or from the digestion of urinary PrP^Sc and not the brain-derived protein has yet to be determined
    • extended digestion of, aggregated, brain-derived PrP^Sc with proteinase K decreases transmissibility , the sensitivity of urine-derived (probably non-aggregated) PrP^Sc to proteinase K is not known

Together the findings above may allow us to:

• develop an assay to screen for animals or humans exposed to PrP^Sc (test for urinary clearance of consumed PrP^Sc)
  • for instance, this may be important if food is discovered that is contaminated with PrP^BSE
  • humans could be screened to confirm or alleviate fears of exposure to prion disease
    
• develop an early marker of TSE transmission in animals
• begin treatment of humans, either exposed to PrP^Sc or with genetic defects, before clinical signs are evident
  • once a treatment is available
• identify animals that may 'carry' a prion disease but may never express symptoms