• Characteristics: Proteinaceous infectious agent that lacks a specific nucleic acid genome A protein-based element of inheritance

• Basic requirements: A self-propagating state of a protein (the prion) that is biologically accessible, but rarely

accumulates spontaneously. Replication by acting on the non-prion state of the protein Capacity to spread to naïve hosts and find new substrate pools for replication.

• Examples Yeast/fungal prions Mammalian TSE prions

Prions

Fragmentation

More prions

Prion state Non-prion state

+conformational

conversion

Yeast prion propagation

• spontaneous formation (rare)• vertical spreading via cell division • horizontal spreading via cytoplasmic exchange (e.g. mating)

Sup35-GFP in yeast cells

Serio and Lindquist 2000

prion-free prion-infected

spontaneous

mating/cytoplasmic

mixing

prion amplification &

cell divisionVertical

Horizontal

Transmission cycle for a naturally spreading mammalian prion disease:Chronic wasting disease

Kraus, Groveman & Caughey, Ann Rev Micro 2013

Horizontal spread contributes to local prevalences of up to 30% in free-ranging deer

Spectrum of prion-like characteristics of misfolded proteins in mammals?

Non-prion protein misfolding

• cytoplasmic propagation (only) • intracellular propagation

• cell-to-cell propagation• tissue-to-tissue propagation• naturally transmissible

• no self-propagation of misfolding within cell or organism• no transmission between individuals

Yeast prion TSE (CWD) prion

• Other TSE diseases• experimentally or iatrogenically

transmissible • Alzheimer’s • type II diabetes• Parkinson’s • Huntington’s • amyotrophic lateral sclerosis • tauopathies• sickle cell anemia• cystic fibrosis • secondary amyloidoses• spinocerebellar ataxias• AA amyloidosis• apolipoprotein AII amyloidosis• many others

?