Prions: Proteinacoeus infectious particle that resist inactivation by procedures that modify nucleic acids Cause transmissible spongiform

encephalopathies in animals and humans Slow progressive fatal course Results in vacuolation of neurons Can cause formation of fibrillar aggregates with amyloid characteristics Human prion diseases Kuru: from cannibalism CJD: iatrogenic, variant, familial, sporadic FSI: familial sporadic insomnia FFI: fatal familial insomnia, germiline mutation GSS: germline mutation

Pathology Neuronal loss, gliosis and brain atrophy Cerebellar atrophy = severe More pronounced loss of granular neurons than Purkinje cells No inflammation Prototypic member: scrapie of sheep (wasting disease)

Mad Cow/ Bovine Spongiform Encephalopathy (BSE) Cows hallucinate Brain found to have spongiform patterns Sheep cows humans Symptoms: Change in behavior (restlessness, aggressiveness) Loss of motor function Loss of appetite Convulsions, blindness, self-mutilation Prion protein is virtually indestructible by heat

Protein concentrates: rendered animal protein feed Inexpensive, high protein Sold in greatest quantities to cattle farmers; also given to other types of animals Ingredients were from animals unfit for human consumption: sick animals and fish

Structure of PrPc and Derivatives

PrPc vs PrPsc

Prion Replication and Pathogenesis PrPc is in equilibrium with PrPsc Fibril fractionation and seeding causes accelerated recruitment of PrPsc Prion fibris (amyloid) are elongated

PrPc in CNS undergoes conformational change PrPsc, which is more resistant to proteinase K digestion

PrPc and PrPsc are identical in primary amino acid sequence