In Ngsk prion protein (PrP)-deficient mice (NP(0/0)), ectopic expression of PrP-like protein Doppel (Dpl) in central neurons induces significant Purkinje cell (PC) death resulting in late-onset ataxia. NP(0/0) PC death is partly prevented by either knocking-out the apoptotic factor BAX or overexpressing the anti-apoptotic factor BCL-2 suggesting that apoptosis is involved in Dpl-induced death. In this study, Western blotting and immunohistofluorescence show that both before and during significant PC loss, the scrapie-responsive gene 1 (Scrg1)--potentially associated with autophagy--and the autophagic markers LC3B and p62 increased in the NP(0/0) PCs whereas RT-PCR shows stable mRNA expression, suggesting that the degradation of autophagic products is impaired in NP(0/0) PCs. At the ultrastructural level, autophagic-like profiles accumulated in somatodendritic and axonal compartments of NP(0/0), but not wild-type PCs. The most robust autophagy was observed in NP(0/0) PC axon compartments in the deep cerebellar nuclei suggesting that it is initiated in these axons. Our previous and present data indicate that Dpl triggers autophagy and apoptosis in NP(0/0) PCs. As observed in amyloid neurodegenerative diseases, upregulation of autophagic markers as well as extensive accumulation of autophagosomes in NP(0/0) PCs are likely to reflect a progressive dysfunction of autophagy that could trigger apoptotic cascades.