title: Autophagy and cell death of Purkinje cells overexpressing Doppel in Ngsk Prnp-deficient mice.
abstract: 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.
authors.affiliation: Institut des Neurosciences Cellulaires et Intégratives, Département Neurotransmission et Sécrétion Neuroendocrine, UMR7168-LC2 CNRS and Université Louis Pasteur, Strasbourg, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Heitz
authors.forename: Nancy J
authors.initials: NJ
authors.lastname: Grant
authors.forename: Raphael
authors.initials: R
authors.lastname: Leschiera
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Haeberlé
authors.forename: Valérie
authors.initials: V
authors.lastname: Demais
authors.forename: Guy
authors.initials: G
authors.lastname: Bombarde
authors.forename: Yannick
authors.initials: Y
authors.lastname: Bailly
mesh_terms: D000818:Animals; D001343:Autophagy; D001369:Axons / Q000473:pathology / Q000648:ultrastructure; D015153:Blotting, Western; D016923:Cell Death; D002525:Cerebellar Cortex / Q000473:pathology / Q000648:ultrastructure; D002529:Cerebellar Nuclei / Q000473:pathology / Q000648:ultrastructure; D002531:Cerebellum / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D003712:Dendrites / Q000473:pathology / Q000648:ultrastructure; D005455:Fluorescent Antibody Technique; D058851:GPI-Linked Proteins; D005838:Genotype; D007150:Immunohistochemistry; D051907:Lysosomal Membrane Proteins / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics; D011328:Prions / Q000096:biosynthesis / Q000235:genetics*; D011689:Purkinje Cells / Q000378:metabolism* / Q000473:pathology* / Q000648:ultrastructure; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051758:Transcription Factor TFIIH; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D005680:gamma-Aminobutyric Acid / Q000378:metabolism; D052118:Lysosomal-Associated Membrane Protein 1
chemical_list: D058851:GPI-Linked Proteins; D051907:Lysosomal Membrane Proteins; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; D011328:Prions; D051758:Transcription Factor TFIIH; D014157:Transcription Factors; D005680:gamma-Aminobutyric Acid; C490981:Gtf2h1 protein, mouse; C052255:Lamp1 protein, mouse; D052118:Lysosomal-Associated Membrane Protein 1; C480860:Map1lc3b protein, mouse; C122036:Prnd protein, mouse; C111496:Scrg1 protein, mouse