Fatal Transmissible Amyloid Encephalopathy: A New Type of Prion Disease Associated with Lack of Prion Protein Membrane Anchoring

Abstract

Prion diseases are fatal neurodegenerative diseases of humans and animals characterized by gray matter spongiosis and accumulation of aggregated, misfolded, protease-resistant prion protein (PrPres). PrPres can be deposited in brain in an amyloid-form and/or non-amyloid form, and is derived from host-encoded protease-sensitive PrP (PrPsen), a protein normally anchored to the plasma membrane by glycosylphosphatidylinositol (GPI). Previously, using heterozygous transgenic mice expressing only anchorless PrP, we found that PrP anchoring to the cell membrane was required for typical clinical scrapie. However, in the present experiments, using homozygous transgenic mice expressing two-fold more anchorless PrP, scrapie infection induced a new fatal disease with unique clinical signs and altered neuropathology, compared to non-transgenic mice expressing only anchored PrP. Brain tissue of transgenic mice had high amounts of infectivity, and histopathology showed dense amyloid PrPres plaque deposits without gray matter spongiosis. In contrast, infected non-transgenic mice had diffuse non-amyloid PrPres deposits with significant gray matter spongiosis. Brain graft studies suggested that anchored PrPsen expression was required for gray matter spongiosis during prion infection. Furthermore, electron and light microscopic studies in infected transgenic mice demonstrated several pathogenic processes not seen in typical prion disease, including cerebral amyloid angiopathy and ultrastructural alterations in perivascular neuropil. These findings were similar to certain human familial prion diseases as well as to non-prion human neurodegenerative diseases, such as Alzheimer's disease.

Induction of ligand-specific PrPCsignaling in human neuronal cells

“…9 While subsequent studies showed that anchorless PrP expressed at 2-fold greater levels and exposed to PrP Sc will result in disease, this disease displays many distinct characteristics from classical, GPI-anchored prion disease. 10,11 This observation is essential in separating protein aggregation from disease pathology and suggests the deleterious effects of TSEs are associated with a change in information transmitted across the membrane. Specifically, the dual requirement for conversion to PrP Sc , as well as the association with lipid rafts suggest a subversion of the normal function of PrP C upon misfolding to PrP Sc that involves distortion of signaling events.…”

Dissociation of recombinant prion autocatalysis from infectivity

“…17 In vivo, loss of the PrP GPI anchor appears to have only a modest effect on PrP Sc structure, 23 but significantly alters its biochemical properties, leading to the production of large, fibrillar aggregates. 24 Interestingly, the experimental addition of a GPI anchor to the amyloidogenic yeast protein Sup35p appears to have an analogous biochemical influence, promoting the formation of non-fibrillar aggregates with ultrastructural similarity to PrP Sc . 25 Recent work has shown that anchorless PrP Sc more readily crosses a species barrier.…”

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

“…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).…”

“…In most instances, PrPSc is membrane-bound as granular, diffuse, nonfibrillar structures, with amyloid plaques only manifesting in certain TSE diseases, such as kuru, Gerstmann-StrausslerScheinker disease, variant Creutzfeldt-Jakob disease, and a minority of sporadic Creutzfeldt-Jakob disease cases (14,(21)(22)(23)(24)(25). The effect of GPI anchoring of PrP on TSE pathogenesis and infectivity has been investigated using a transgenic mouse that expresses PrPC lacking a GPI anchor (26,27). In these mice, dense amyloid PrPSc deposits form following infection.…”

“…In these mice, dense amyloid PrPSc deposits form following infection. This is accompanied by altered clinical disease, prolonged incubation period, and poor susceptibility to peripheral routes of infection, suggesting that the GPI anchor strongly influences TSE pathogenesis (27,28).…”