New insights into Doppel neurotoxicity using cerebellar organotypic cultures from prion protein-deficient mice

Elucidation of the mechanisms underlying neurodegeneration and neuronal death is a key challenge in elaborating innovative therapies for cerebral pathologies. In the prion protein (PrPc)-deficient Nagasaki (Ngsk) mutant mouse, the ectopic expression of the neurotoxic PrPc-like protein doppel (Dpl) results in the progressive loss of cerebellar Purkinje cells (PCs). According to our recent data, a mitochondrial apoptotic pathway, as well as a blockade of autophagic flux, could mediate Dpl neurotoxicity in the PCs of Ngsk mice. Here, the development and survival of these neurons were analysed in cerebellar organotypic cultures and, as observed in vivo, a degenerative process resulting in growth deficits and neuronal death is activated in the Ngsk PC in these cultures. This suggests that organotypic cultures may be a suitable model for characterizing the mechanisms underlying Dpl neurotoxicity in the Ngsk PCs.