Endogenous prion protein conversion is required for prion-induced neuritic alterations and neuronal death.
Prions cause fatal neurodegenerative conditions and result from the conversion of host-encoded cellular prion protein (PrP(C)) into abnormally folded scrapie PrP (PrP(Sc)). Prions can propagate both in neurons and astrocytes, yet neurotoxicity mechanisms remain unclear. Recently, PrP(C) was proposed to mediate neurotoxic signaling of β-sheet-rich PrP and non-PrP conformers independently of conversion. To investigate the role of astrocytes and neuronal PrP(C) in prion-induced neurodegeneration, we set up neuron and astrocyte primary cocultures derived from PrP transgenic mice. In this system, prion-infected astrocytes delivered ovine PrP(Sc) to neurons lacking PrP(C) (prion-resistant), or expressing a PrP(C) convertible (sheep) or not (mouse, human). We show that interaction between neuronal PrP(C) and exogenous PrP(Sc) was not sufficient to induce neuronal death but that efficient PrP(C) conversion was required for prion-associated neurotoxicity. Prion-infected astrocytes markedly accelerated neurodegeneration in homologous cocultures compared to infected single neuronal cultures, despite no detectable neurotoxin release. Finally, PrP(Sc) accumulation in neurons led to neuritic damages and cell death, both potentiated by glutamate and reactive oxygen species. Thus, conversion of neuronal PrP(C) rather than PrP(C)-mediated neurotoxic signaling appears as the main culprit in prion-induced neurodegeneration. We suggest that active prion replication in neurons sensitizes them to environmental stress regulated by neighboring cells, including astrocytes.
UR892, Virologie et Immunologie Moléculaires, Institut National de Recherche Agronomique, Jouy-en-Josas, France. sabrina.cronier@jouy.inra.fr
Sabrina
S
Cronier
Julie
J
Carimalo
Brigitte
B
Schaeffer
Emilie
E
Jaumain
Vincent
V
Béringue
Marie-Christine
MC
Miquel
Hubert
H
Laude
Jean-Michel
JM
Peyrin
D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism; D016923:Cell Death; D002478:Cells, Cultured; D018920:Coculture Techniques; D017077:Culture Media, Conditioned; D005455:Fluorescent Antibody Technique; D051379:Mice; D008822:Mice, Transgenic; D016501:Neurites; D009474:Neurons / Q000166:cytology*; D011328:Prions / Q000502:physiology*
D017077:Culture Media, Conditioned; D011328:Prions