Doppel induces autophagic stress in prion protein-deficient Purkinje cells.

The ectopic expression of the prion protein homologue Doppel (Dpl) in brain neurons causes progressive cerebellar Purkinje cell death in prion protein-deficient Ngsk mice (NP0/0). The neurotoxicity caused by Dpl involves Bax-dependent apoptotic pathways as well as other yet to be characterized cell death mechanisms in the NP0/0 Purkinje cells. These neurons display increased amounts of several autophagy-related molecules such as the scrapie-responsive gene one (Scrg1), LC3B-II and p62 without showing any changes in mRNA expression; in addition, autolysosomes accumulate in all neuronal compartments including axon terminals. This suggests that Dpl toxicity provokes impairment in the autophagic flux, which may trigger apoptosis in these neurons, similar to the way neurodegeneration is thought to occur in Alzheimer and prion diseases. Purkinje cells feature early axonal autophagy in both NP0/0 and GluRδ2Lc mutants, but no signs of autophagic flux impairment are evident in GluRδ2Lc Lurcher, suggesting that dif...