Endogenous PrP conversion is required for prion-induced neuritic alterations and neuronal death

Sabrina Cronier (1) , Julie Carimalo (2) , Brigitte Schaeffer (3) , Marie-Christine Miquel (4) , Hubert H. Laude (1) , Jean-Michel Peyrin (5)

1 VIM (UR 0892) - Unité de recherche Virologie et Immunologie Moléculaires
2 UMG - University Medical Center Göttingen
3 MIA-JOUY - Unité de biométrie et intelligence artificielle de Jouy
4 LMPM - Métabolisme Plasticité et Mitochondrie [lié à l'ex IFR 31]
5 NPA - Neurobiologie des processus adaptatifs

Background: Mechanisms involved in prion induced neuronal death are still enigmatic. In vivo, both neurons and astrocytes support prion propagation leading to abnormal production of a misfolded protein called scrapie prion protein (PrPSc). Although crucial for prion replication and accumulation of aggregated PrPSc, the role of the normal form of prion protein,the cellular PrP (PrPC), is still controversial in prion-induced neurotoxicity. Objectives : In this study we investigated the role of neuronal PrPC and the contribution of astrocytes in prion-induced neuronal death. Methods: We have previously shown that prions could be efficiently propagated in primarily cultured neurons and astrocytes (Cronier et al. 2004). Here, we have set up a model in which neurons devoid of PrPC or expressing PrPC from different species are cocultured with prion-infected astrocytes that continuously deliver physiological concentrations of PrPSc. Results : In these conditions, we showed that scrapie-infected astrocytes exacerbate prion-induced cell death solely in neurons expressing transconformable PrPC. Although infectious, conditioned medium of prion-infected astrocytes did not display any acute neuronal toxicity. However PrPSc accumulation in neurons led to neuritic damage and cell death associated with an increased sensitivity to glutamate and reactive oxygen species. Discussion : Our results indicate that interaction between neuronal PrPC and PrPSc is not sufficient to induce neuronal death but that PrPC transconformation is required for prion-associated neurotoxicity. In addition, it is unlikely that a dysfunction of prion-infected astrocytes is involved in the initiation of neuronal death process induced by prions. Altogether, our findings support the view that prion infection and subsequent PrPC transconformation trigger impairment of neuronal homeostasis by sensitizing neurons to environmental stress that are regulated by neighbouring cells including astrocyte.

Mots clés: astrocutes; PrPC; astrocutes

Mots clés: prion; neuronal; NEUROBIOLOGIE; neuronale

Domaines: Mathématiques [math]; Informatique [cs]

Sabrina Cronier, Julie Carimalo, Brigitte Schaeffer, Marie-Christine Miquel, Hubert H. Laude, et al.. Endogenous PrP conversion is required for prion-induced neuritic alterations and neuronal death. Prion 2009, Sep 2009, Chalkidiki, Greece. ⟨hal-02753346⟩