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Autophagy and Cell Death of Purkinje Cells Overexpressing Doppel in Ngsk Prnp‐deficient Mice

In Ngsk prion protein (PrP)‐deficient mice (NP0/0), ectopic expression of PrP‐like protein Doppel (Dpl) in central neurons induces significant Purkinje cell (PC) death resulting in late‐onset ataxia. NP0/0 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 NP0/0 PCs whereas RT‐PCR shows stable mRNA expression, suggesting that the degradation of autophagic products is impaired in NP0/0 PCs. At the ultrastructural level, autophagic‐like profiles accumulated in somatodendritic and axonal compartments of NP0/0, but not wild‐type PCs. The most robust autophagy was observed in NP0/0 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 NP0/0 PCs. As observed in amyloid neurodegenerative diseases, upregulation of autophagic markers as well as extensive accumulation of autophagosomes in NP0/0 PCs are likely to reflect a progressive dysfunction of autophagy that could trigger apoptotic cascades.