Prion Infections and Anti-PrP Antibodies Trigger Converging Neurotoxic Pathways

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Prion diseases are a group of infectious, invariably fatal neurodegenerative diseases. Progress in developing therapeutics is slow, partly because animal models of prion diseases require stringent biosafety and are very slow. We recently found that treatment of cerebellar slices with antibodies targeting the globular domain (GD ligands) of the prion protein (PrP) is neurotoxic. Here we compared this model to prion infection, and describe striking similarities. Both models involved the production of reactive oxygen species, and antioxidants could reverse the toxicity in cerebellar slices and even prolong the survival time of prion-infected mice. Antibodies targeting the flexible tail of PrP that prevent toxicity of GD ligands reduced the toxicity induced by prions. Endoplasmic reticulum stress, which is involved in prion toxicity, is also found in GD-ligand induced neurotoxicity. Finally, changes of gene expression were similar in both models. We conclude that prion infection and GD ligands use converging neurotoxic pathways. Because GD ligands induce toxicity within days rather than months and do not pose biosafety hazards, they may represent a powerful tool for furthering our understanding of prion pathogenesis and also for the discovery of antiprion drugs.

Vyšlo v časopise: Prion Infections and Anti-PrP Antibodies Trigger Converging Neurotoxic Pathways. PLoS Pathog 11(2): e32767. doi:10.1371/journal.ppat.1004662
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004662

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