Abstract
Prions are the infectious agents causing transmissible spongiform encephalopathies (TSE), progressive, inexorably lethal neurological diseases. Antibodies targeting the globular domain (GD) of the cellular prion protein PrPC trigger a neurotoxic syndrome morphologically and molecularly similar to prion disease. This phenomenon raises the question whether such antibodies induce infectious prions de novo. Here we exposed cerebellar organotypic cultured slices (COCS) to the neurotoxic antibody, POM1. We then inoculated COCS homogenates into tga20 mice, which overexpress PrPC and are commonly utilized as sensitive indicators of prion infectivity. None of the mice inoculated with COCS-derived lysates developed any signs of disease, and all mice survived for at least 200 days post-inoculation. In contrast, all mice inoculated with bona fide prions succumbed to TSE after 55–95 days. Post-mortem analyses did not reveal any signs of prion pathology in mice inoculated with POM1-COCS lysates. Also, lysates from POM1-exposed COCS were unable to convert PrP by quaking. Hence, anti-GD antibodies do not catalyze the generation of prion infectivity. These data indicate that prion replication can be separated from prion toxicity, and suggest that anti-GD antibodies exert toxicity by acting downstream of prion replication.
Highlights
Prion diseases are fatal neurodegenerative diseases that rely on the seeded propagation of an aggregated form of the cellular prion protein PrPC [1]
NeuN immunofluorescent stainings, which identify neurons, showed widespread neuronal degeneration in cerebellar organotypic cultured slices (COCS) treated with scFvPOM1, but not in COCS treated with antibody that had been preemptively blocked with recPrP23-230 (Fig 1A)
The neurotoxic antibody POM1 mimics the typical prion pathology with spongiform change, neuronal loss, astrogliosis, and microglial activation, and triggers transcriptomic perturbations similar to those observed in prion diseases [4]
Summary
Prion diseases are fatal neurodegenerative diseases that rely on the seeded propagation of an aggregated form of the cellular prion protein PrPC [1]. The aggregated form, denoted PrPSc, is typically resistant to limited digestion with proteinase K (PK). The pathology triggered by prion infections, consisting of spongiosis, neuronal loss, astrogliosis, and microglial activation, is faithfully reproduced by administration of anti-prion antibodies targeting conformational epitopes on the globular domain (GD) of PrPC [2, 3]. Toxicity requires the long flexible tail (FT) of PrPC, and antibodies against the octapeptide repeat (OR) domain of the FT prevent the toxicity of anti-GD antibodies and antagonize neurodegeneration in prion infections [4]. Therapeutic compounds conferring anti-prion protection are frequently effective against toxic.
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