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 (PrPC) into abnormally folded scrapie PrP (PrPSc). Prions can propagate both in neurons and astrocytes, yet neurotoxicity mechanisms remain unclear. Recently, PrPC was proposed to mediate neurotoxic signaling of beta-sheet-rich PrP and non-PrP conformers independently of conversion. To investigate the role of astrocytes and neuronal PrPC 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 PrPC (prion-resistant), or expressing a PrPC convertible (sheep) or not (mouse, human). We show that interaction between neuronal PrPC and exogenous PrPSc was not sufficient to induce neuronal death but that efficient PrPC 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, PrPSc accumulation in neurons led to neuritic damages and cell death, both potentiated by glutamate and reactive oxygen species. Thus, conversion of neuronal PrPC rather than PrPC-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.-Cronier, S., Carimalo, J., Schaeffer, B., Jaumain, E., Beringue, V., Miquel, M.-C., Laude, H., Peyrin, J.-M. Endogenous prion protein conversion is required for prion-induced neuritic alterations and neuronal death. FASEB J. 26, 3854-3861 (2012). www.fasebj.org