Journal Article

In Vitro and In Vivo Neurotoxicity of Prion Protein Oligomers

Vidal, Catherine, Kaiser-Schulz, Gunnar, Salès, Nicole, Wopfner, Franziska, Simoneau, Steve, Comte, Julien, Grosclaude, Jeanne, Lasmézas, Corinne Ida, Rezaei, Human, Fournier, Jean-Guy, Lefebvre-Roque, Maxime, Schätzl, Hermann

2007

Overview

The mechanisms underlying prion-linked neurodegeneration remain to be elucidated, despite several recent advances in this field. Herein, we show that soluble, low molecular weight oligomers of the full-length prion protein (PrP), which possess characteristics of PrP to PrPsc conversion intermediates such as partial protease resistance, are neurotoxic in vitro on primary cultures of neurons and in vivo after subcortical stereotaxic injection. Monomeric PrP was not toxic. Insoluble, fibrillar forms of PrP exhibited no toxicity in vitro and were less toxic than their oligomeric counterparts in vivo. The toxicity was independent of PrP expression in the neurons both in vitro and in vivo for the PrP oligomers and in vivo for the PrP fibrils. Rescue experiments with antibodies showed that the exposure of the hydrophobic stretch of PrP at the oligomeric surface was necessary for toxicity. This study identifies toxic PrP species in vivo. It shows that PrP-induced neurodegeneration shares common mechanisms with other brain amyloidoses like Alzheimer disease and opens new avenues for neuroprotective intervention strategies of prion diseases targeting PrP oligomers.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Alzheimer's disease / Animals / Antibodies, Blocking - pharmacology / Antibodies, Monoclonal - pharmacology / Apoptosis - drug effects / Brain / Brain - drug effects / Brain - metabolism / Brain - pathology / Cells, Cultured / Chemical properties / Creutzfeldt-Jakob disease / Eukaryotes / Experiments / Female / Hypotheses / Insomnia / Intracellular Membranes - drug effects / Life Sciences / Mice / Mice, Inbred C57BL / Mice, Knockout / Microscopy / Molecular weight / Mus (Mouse) / Neurodegeneration / Neurological Disorders / Neurons - drug effects / Neurons - metabolism / Neurons - pathology / Neurotoxicity / Oligomers / Prion Diseases - chemically induced / Prion Diseases - metabolism / Prion Diseases - pathology / Prions / Prions - chemistry / Prions - immunology / Prions - metabolism / Prions - toxicity / Protein Isoforms / Protein Structure, Secondary / Proteins / Spongiform encephalopathies / Toxicity / Vertebrates