Mechanism of PrP‐Amyloid Formation in Mice Without Transmissible Spongiform Encephalopathy

Abstract

Gerstmann-Sträussler-Scheinker (GSS) P102L disease is a familial form of a transmissible spongiform encephalopathy (TSE) that can present with or without vacuolation of neuropil. Inefficient disease transmission into 101LL transgenic mice was previously observed from GSS P102L without vacuolation. However several aged, healthy mice had large plaques composed of abnormal prion protein (PrPd). Here we perform the ultrastructural characterisation of such plaques and compare them with PrPd aggregates found in TSE caused by an infectious mechanism. PrPd plaques in 101LL mice varied in maturity with some being composed of deposits without visible amyloid fibrils. PrPd was present on cell membranes in the vicinity of all types of plaques. In contrast to the unicentric plaques seen in infectious murine scrapie the plaques seen in the current model were multi-centric and were initiated by proto-fibrillar forms of PrPd situated on oligodendroglia, astrocytes and neuritic cell membranes. We speculate that the initial conversion process leading to plaque formation begins with membrane-bound PrPC but that subsequent fibrillisation does not require membrane attachment. We also observed that the membrane alterations consistently seen in murine scrapie and other infectious TSEs were not observed in 101LL mice with plaques suggesting differences in the pathogenesis of these conditions.

Influence of Breed and Genotype on the Onset and Distribution of Infectivity and Disease-associated Prion Protein in Sheep Following Oral Infection with the Bovine Spongiform Encephalopathy Agent

“…While PrP d /PrP res is widely considered as the best surrogate marker for TSE infections, its relationship with actual infectivity is not always clear, either in qualitative or quantitative terms. Thus, in some studies infectivity has been shown without significant PrP res detection BalkemaBuschmann et al, 2011;Miyazawa et al, 2011), while in other TSE models PrP d can be demonstrated without an apparent link to infectivity (Piccardo et al, 2007;Jeffrey et al, 2012). Other studies of natural sheep scrapie and experimental sheep BSE indicate that quantitative test results for PrP d /PrP res do not correlate with TSE infectious titres with any high degree of precision .…”

Dissociation of Prion Protein Amyloid Seeding from Transmission of a Spongiform Encephalopathy

“…We also failed to induce the plaque-forming phenotype in wild-type mice. In addition, previous ultrastructural analysis showed that cell membrane alterations consistently seen in murine scrapie and other infectious prion diseases were not present in 101LL-8a mice with amyloid plaques, suggesting differences in the pathogenesis of these conditions (9). Therefore, our model would appear to represent a different mechanism from what is generally understood as infection.…”

“…Studies using 263K hamster scrapie have shown a strong correlation between PrP TSE and infectivity (1)(2)(3). However, prion diseases can develop with high levels of infectivity and very low levels of PrP deposition and, conversely, PrP TSE accumulates in the brain in some situations unaccompanied by the other typical neuropathologic changes or any clinical signs of disease (4)(5)(6)(7)(8)(9)(10). Thus, both the molecular basis of prion propagation between individuals and the mechanism by which PrP C converts into PrP TSE and spreads from cell to cell in the affected host remain unclear.…”

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

“…TSE-associated GPI-anchored aggregates composed of misfolded prion protein usually appear as small, diffuse assemblies that do not appear to be amyloid fibrils (14,15,22). However, PrPSc can also form amyloid, demonstrated by the presence of extracellular plaques in some cases of TSE and in mice genetically modified to express anchorless prion protein, following extraction or release from cell membranes and in vitro (26,37,(82)(83)(84). Thus, similar to the observations made in this study, GPI anchor-mediated membrane association of the prion protein appears to prevent amyloid fibril formation.…”