Prions – Focused Exam Notes

Definition & Key Features

• Prions: infectious, misfolded host proteins causing transmissible spongiform encephalopathies (TSEs)
• No nucleic-acid genome, <100\,\text{nm} in size
• Cannot be cultured in vitro; elicit no immune/inflammatory response
• Extremely resistant to heat, standard disinfectants, irradiation; inactivated by high phenol, periodate, $\text{NaOH}$, $\text{NaClO}$
• Incubation can extend to $\approx 35$ years

Major Human & Animal TSEs

• Humans: kuru, sporadic CJD, familial CJD, variant CJD (vCJD)
• Animals: bovine spongiform encephalopathy (BSE; “mad cow”), scrapie (sheep)

Molecular Pathogenesis

• Normal neuronal glycoprotein: $PrP^C$ (linear, enzyme-susceptible, membrane-bound)
• Pathogenic isoform: $PrP^{Sc}$ (globular, protease-resistant)
• $PrP^{Sc}$ binds $PrP^C$ → converts it to $PrP^{Sc}$ → self-propagating cycle
• Aggregated $PrP^{Sc}$ forms amyloid fibrils/plaques → neuronal loss → spongiform brain appearance

Transmission Routes

• Oral ingestion of contaminated tissue (e.g., BSE→vCJD; kuru via cannibalism)
• Contaminated medical products or instruments (blood, grafts, neurosurgery tools)
• Possible but low mother-to-fetus transfer
• Prions survive digestion; uptake across intestine, carriage in white blood cells

Zoonotic Considerations

• Cross-species spread less efficient but significant (BSE → humans; scrapie → cattle)
• vCJD: younger patients, shorter incubation; outbreak linked to meat from BSE-infected cattle fed scrapie-contaminated offal

Genetic Susceptibility

• PRNP gene on chromosome $20$ encodes $PrP^C$
• Homozygosity at codon $129$ polymorphism strongly associated with vCJD and kuru cases
• Heterozygosity may confer resistance or prolonged incubation
• Sheep breeds exhibit variable scrapie resistance; similar findings in mice

Diagnosis

• Clinical clue: rapidly progressive dementia → death <1 year in $\sim 90\%$ of cases
• Supportive tests:
  • MRI: cortical/basal ganglia degeneration (non-specific)
  • Immunoblot of tonsil or blood for $PrP^{Sc}$
  • Genetic testing for PRNP codon $129$ status (risk, not confirmation)
  • Definitive post-mortem neuropathology
• New in vivo assay: RT-QuIC on CSF – recombinant $PrP$ + patient sample + dye + shaking → fibril-induced fluorescence indicates $PrP^{Sc}$ presence

Treatment & Prevention

• No curative therapy; care is supportive
• Experimental: monoclonal antibody PRN100 showed early promise (2022)
• Prevention: strict feed regulations (no offal), food-chain surveillance, rigorous decontamination of instruments