The
transmissible spongiform encephalopathies (TSEs) or
prion diseases of animals are characterised by CNS spongiform change,
gliosis and the accumulation of disease-associated forms of
prion protein (
PrP(d)). Particularly in ruminant
prion diseases, a wide range of morphological types of
PrP(d) depositions are found in association with neurons and glia. When light microscopic patterns of
PrP(d) accumulations are correlated with sub-cellular structure, intracellular
PrP(d) co-localises with lysosomes while non-intracellular
PrP(d) accumulation co-localises with cell membranes and the extracellular space. Intracellular lysosomal
PrP(d) is N-terminally truncated, but the site at which the
PrP(d) molecule is cleaved depends on strain and cell type. Different
PrP(d) cleavage sites are found for different cells infected with the same agent indicating that not all
PrP(d) conformers code for different
prion strains. Non-intracellular
PrP(d) is full-length and is mainly found on plasma-lemmas of neuronal perikarya and dendrites and glia where it may be associated with
scrapie-specific membrane pathology. These membrane changes appear to involve a redirection of the predominant axonal trafficking of normal cellular PrP and an altered endocytosis of
PrP(d).
PrP(d) is poorly excised from membranes, probably due to increased stabilisation on the membrane of
PrP(d) complexed with other membrane
ligands.
PrP(d) on plasma-lemmas may also be transferred to other cells or released to the extracellular space. It is widely assumed that
PrP(d) accumulations cause neurodegenerative changes that lead to clinical disease. However, when different animal
prion diseases are considered, neurological deficits do not correlate well with any morphological type of
PrP(d) accumulation or perturbation of
PrP(d) trafficking. Non-
PrP(d)-associated neurodegenerative changes in TSEs include vacuolation, tubulovesicular bodies and terminal axonal degeneration. The last of these correlates well with early neurological disease in mice, but such changes are absent from large animal
prion disease. Thus, the proximate cause of clinical disease in animal
prion disease is uncertain, but may not involve
PrP(d).