This page summarises one review, Manka and colleagues (2023, published online August 2022). About 100,000 of its 143,000 characters were read, and later primary work is not covered. The mouse and hamster findings below come from laboratory strains and do not describe human disease subtypes, which are covered on the mechanisms overview.
What is a prion strain?
The review defines strains as transmissible variants that produce distinct clinicopathological phenotypes in the same host. It proposes that strains are encoded by distinct misfolded PrP conformations and assembly states, and not by a difference in the host protein sequence.
How are strains distinguished?
After proteinase K digestion, the protease-resistant core, PrP 27-30, gives a broadly similar band pattern across strains. Strains differ in the sizes of proteolytic fragments and in glycoform ratios. For example, the mouse strain RML has fewer diglycosylated and more mono- and non-glycosylated PrP, while hamster 263K reflects the natural glycoform abundance. Strains are also distinguished by bioassay, meaning by the disease they cause in animals.
What has cryo-EM shown?
Ex vivo fibrils of RML (mouse) and 263K (hamster) share a similar architecture: single-protofilament, left-handed helical fibrils with a parallel in-register intermolecular beta-sheet. This holds despite eight sequence differences between mouse and hamster PrP. The N-terminal lobe is more conserved between the strains than the C-terminal lobe, which carries the glycans and the GPI anchor. Differences in a hydrophobic cluster and in the arrangement of the C-terminus distinguish the two strains. RML protofibrils can pair side by side into two-protofilament fibrils, which has not been reported for 263K. Recombinant PrP fibrils have not reproduced these ex vivo folds and are not infectious.
What is unresolved?
The authors identify these open questions:
- Whether protofilament pairing is specific to strains that select certain glycoforms or is a general feature of prions. The difference from 263K may relate to purification methods.
- How strain-specific glycoform ratios are maintained, since the single-protofilament structure does not clearly explain glycan selectivity.
- The identity of the neurotoxic PrP species, which appears distinct from infectious fibrils. See neurotoxicity.
- How authentic prions and alternative PrP amyloids contribute to the varied phenotypes of inherited prion disease.
- How high-resolution structures of prions in cells or tissue can be obtained. The authors suggest correlative light and electron cryo-tomography.
See also the mechanisms hub.