Infectious Particles
Agent Hypotheses
Dominant belief
Normal host prion protein (PrP) spontaneously converts into an infectious amyloid, i.e., a “prion”;
Alternative view
TSE agents are environmental pathogens with a genome that encodes different agent strains;
These infectious agents need cell PrP to survive, and they provoke PrP amyloid as a late defense mechanism.
A) no infection without PrP host receptor; B) most agents induce same PrP-res; C) Amyloid stymies agent
Current Status (3/2014)
Attempts to fabricate an infectious PrP in a test tube
No reproducible infectivity for any pure PrP, including recombinant PrP (rPrP); more than 100 independent experiments fail to generate any infectivity from rPrP
Update: Dec 2015 Collinge lab reported 20,000 failed attempts to make rPrP infectious (Open Biol. 2015 Dec;5(12):150165. doi: 10.1098/rsob.150165) in contrast to previous Science publications.
Additional new data
- Removal of PrP in brain homogenates does not reduce the infectivity PMID 21793014
- When the “infectious” PrP amyloid increases, infectivity falls by 10,000 fold PMID 22509412
- All infectious preparations contain circular DNAs of >500nt by molecular analysis PMID 21165784
- CJD and scrapie agent particles, as viral structures, require nucleic acids to infect cells Download PDF
- Infectious particles, stress, and induced prion amyloids Download PDF
- Continuous production of prions after infectious particles are eliminated Download PDF
Are "established" Prion claims accurate?
| Claim | Experiment | Comment |
| 1) "PrPSc (PrP-res amyloid) is proportional to titer" | FALSE | diverse data from many labs falsify |
| 2) "Procedures that hydrolyze PrPSc inactivate prions" | TRUE | These also inactivate viruses |
| 3) "No evidence exists for a virus-like particle" | FALSE | discrete ~25nm viral particle |
| 4) "Transmissible particles are devoid of nucleic acid" | FALSE | all infectious matter contains long DNA |
| 5) "PrP gene mutations cause formation of PrPSc" | FALSE | toxic pathology, but not PrPSc |
| 6) "PrP gene mutations cause transmissible disease" | FALSE | Contamination with scrapie & irreproducible |
| 7) "Prion diversity is enciphered by PrPSc" folding | FALSE | unfolding PrP-res: no effect on strain or titer |
| 9) "No immune response to foreign agent" | FALSE | Early innate immune responses before PrP-res |
| 10) "PrPSc associated with pathology" | TRUE | PrPSc is a late response to infection |
| 11) Protein X binds PrP to make it infectious | X not found | PrP itself not infectious; X is probably a virus |
| 12) "Prions defy the rules of protein structure" | TRUE | also of thermodynamics |
| 13) CJD infectious agent arises spontaneously | No evidence for | An old & disproven concept of infection |
| 14) recombinant PrP can be made infectious | FALSE | Irreproducible: numerous failed attempts |