In Vitro and In Vivo Neurotoxicity of Prion Protein Oligomers

PLoS Pathogens

Julien Comte¹  Franziska Wopfner¹  Steve Simoneau¹  Maxime Lefebvre-Roque¹  Catherine Vidal²  Nicole Salès²  Human Rezaei³  Hermann Schätzl³  Jean-Guy Fournier⁴  Jeanne Grosclaude⁵  Gunnar Kaiser-Schulz⁵  Corinne Ida Lasmézas⁵ 

[1] Commissariat à l'Energie Atomique, Fontenay-aux-Roses, France;Department of Infectology, The Scripps Research Institute, Jupiter, Florida, United States of America;Institut National de la Recherche Agronomique, Jouy-en-Josas, France;Institut Pasteur, Paris, France;Institute of Virology, Technical University of Munich, Munich, Germany

关键词: Oligomers;    Neurons;    Toxicity;    Amyloid proteins;    Neuronal death;    Apoptosis;    Animal prion diseases;    Mouse models;   

DOI  :  10.1371/journal.ppat.0030125

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY