In vitro and in vivo neurotoxicity of prion protein oligomers.
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.
Simoneau
Steve
S
Commissariat à l'Energie Atomique, Fontenay-aux-Roses, France.
Rezaei
Human
H
Salès
Nicole
N
Kaiser-Schulz
Gunnar
G
Lefebvre-Roque
Maxime
M
Vidal
Catherine
C
Fournier
Jean-Guy
JG
Comte
Julien
J
Wopfner
Franziska
F
Grosclaude
Jeanne
J
Schätzl
Hermann
H
Lasmézas
Corinne Ida
CI
D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D005260:Female; D007425:Intracellular Membranes / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D017096:Prion Diseases / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D011328:Prions / Q000737:chemistry / Q000276:immunology / Q000378:metabolism / Q000633:toxicity*; D020033:Protein Isoforms; D017433:Protein Structure, Secondary