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 hostencoded 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 PrPsc 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^Sc 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. [ABSTRACT FROM AUTHOR]