Neurotoxic Antibodies against the Prion Protein Do Not Trigger Prion Replication

PLoS One. 2016 Sep 29;11(9):e0163601. doi: 10.1371/journal.pone.0163601. eCollection 2016.


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.

Grant support

Adriano Aguzzi is the recipient of an Advanced Grant (PRION2020) of the European Research Council (, a European Union Framework 7 Grant (NEURINOX,, the Swiss National Foundation (310030B_160329,, the Clinical Research Priority Programs “Small RNAs” and “Human Hemato-Lymphatic Diseases” (, (PrionX and SynucleiX), and the Novartis Research Foundation ( Katrin Frauenknecht is the recipient of a Career Development Award from the Stavros Niarchos Foundation ( Simone Hornemann is the recipient of grants from (SynucleiX) and the University Hospital of Zurich (Innovationspool, Manuela Pfammatter is a recipient of the career development award "Candoc" of the University of Zurich. Assunta Senatore is a recipient of the career development award "Postdoc" of the University of Zurich. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.