Cellular and sub-cellular pathology of animal prion diseases: relationship between morphological changes, accumulation of abnormal prion protein and clinical disease

Abstract

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).

Profoundly different prion diseases in knock-in mice carrying single PrP codon substitutions associated with human diseases

“…Surprisingly, the PrP res aggregates in CJD brains that were observed by light microscopy were not detected by EM. Although it seems counterintuitive, this distinction has been reported by others (19). In sharp contrast, PrP res aggregates were not detected in FFI brains by using standard procedures.…”

“…2B). In humans, spongiosis is a rare feature that distinguishes most of the prion diseases, including CJD but not FFI, from other neurodegenerative diseases (19). Other notable differences between the mice also characteristically distinguish CJD and FFI diseases in humans.…”

Glycosylphosphatidylinositol Anchoring Directs the Assembly of Sup35NM Protein into Non-fibrillar, Membrane-bound Aggregates

“…In prion-infected tissues, PrPSc aggregates may be membrane-associated, either on the cell surface or within intracellular vesicles, or may be deposited in the form of amyloid plaques in the extracellular space (11,14,15). "Amyloid" refers to an ordered fibrillar structure in which hydrogen-bonded ␤-sheets are oriented perpendicular to the fibril axis, forming an architecture known as cross-␤ (16).…”

“…43 and 44; reviewed in Ref. 15). This technique has also revealed that membrane-bound PrPSc gives rise to unusual membrane lesions, in particular plasma membrane invaginations on neurons and astrocytes (15,45,46).…”

“…15). This technique has also revealed that membrane-bound PrPSc gives rise to unusual membrane lesions, in particular plasma membrane invaginations on neurons and astrocytes (15,45,46). No similar membrane lesions were observed in the GPI anchorless PrPC mouse model, suggesting that only GPI-anchored PrPSc is able to induce such pathology (26,27).…”