Doppel induces autophagic stress in prion protein-deficient Purkinje cells

Heitz, Stéphane; Grant, Nancy J.; Bailly, Yannick

doi:10.4161/auto.5.3.7882

Cited by 11 publications

(12 citation statements)

References 13 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, in their results, the OD values of ubiquitinated proteins ranged from 0.05 and induces neuron death. 27,28 Hence, these connections between prion proteins and autophagy prompted us to determine whether prion infection can induce the host autophagy response. In this report, through the use of western blots, immunohistochemistry and immunofluorescence assays for specific markers of the autophagic system, autophagosome formation was detected in brains during the pathogenesis of scrapie experimental hamsters and human genetic prion diseases.…”

Section: Discussionmentioning

confidence: 99%

Activation of the macroautophagic system in scrapie-infected experimental animals and human genetic prion diseases

Tian

Wang

et al. 2012

Autophagy

View full text Add to dashboard Cite

Section: Discussionmentioning

confidence: 99%

Activation of the macroautophagic system in scrapie-infected experimental animals and human genetic prion diseases

Tian

Wang

et al. 2012

Autophagy

View full text Add to dashboard Cite

“…The ). It was demonstrated that before and during neuronal loss, neighboring cell surface-bound Dpl activates death receptors, leading to the production of ROS in a calcium-dependent mechanism, then several autophagyrelated molecules such as the Scrg1 (scrapie-responsive gene one), LC2-II, and p62 were increased without showing any changes in mRNA expression [81]. These results suggest that Dpl toxicity might impair the ultimate steps of autophagic degradation in NP 0/0 Purkinje cell, which may trigger the apoptotic cascade by a progressive dysfunctional autophagy [82].…”

Section: Autophagy In Prion Diseasesmentioning

confidence: 99%

Role of autophagy in prion protein-induced neurodegenerative diseases

Yao¹,

Zhao²,

Khan³

et al. 2013

ABBS

View full text Add to dashboard Cite

Prion diseases, characterized by spongiform degeneration and the accumulation of misfolded and aggregated PrP Sc in the central nervous system, are one of fatal neurodegenerative and infectious disorders of humans and animals. In earlier studies, autophagy vacuoles in neurons were frequently observed in neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's diseases as well as prion diseases. Autophagy is a highly conserved homeostatic process by which several cytoplasmic components ( proteins or organelles) are sequestered in a doublemembrane-bound vesicle termed 'autophagosome' and degraded upon their fusion with lysosome. The pathway of intercellular self-digestion at basal physiological levels is indispensable for maintaining the healthy status of tissues and organs. In case of prion infection, increasing evidence indicates that autophagy has a crucial ability of eliminating pathological PrP Sc accumulated within neurons. In contrast, autophagy dysfunction in affected neurons may contribute to the formation of spongiform changes. In this review, we summarized recent findings about the effect of mammalian autophagy in neurodegenerative disorders, particularly in prion diseases. We also summarized the therapeutic potential of some small molecules (such as lithium, rapamycin, Sirtuin 1 and resveratrol) targets to mitigate such diseases on brain function. Furthermore, we discussed the controversial role of autophagy, whether it mediates neuronal toxicity or serves a protective function in neurodegenerative disorders.

show abstract

“…The same authors showed that the pro-apoptotic effects of Dpl on PCs can be partially counteracted by Bcl-2 overexpression 42 . Recently, they have also described the upregulation of autophagic markers as well as extensive accumulation of autophagosomes in PCs of Ngsk mice, proposing that a progressive dysregulation of autophagy could contribute to PCs loss by triggering apoptotic cascades 43 , 44 . In contrast, other authors failed to detect any ameliorating effect on PCs derived from Bax inactivation in Tg(Dpl) mice in which Dpl is ectopically expressed in the CNS driven by the neural-specific enolase promoter 45 .…”

Section: Discussionmentioning

confidence: 96%

The role of Bax and caspase-3 in doppel-induced apoptosis of cerebellar granule cells

Didonna

Sussman

Benetti

et al. 2012

Prion

View full text Add to dashboard Cite

Doppel (Dpl) protein is a paralog of the prion protein (PrP) that shares 25% sequence similarity with the C-terminus of PrP, a common N-glycosylation site and a C-terminal signal peptide for attachment of a glycosylphophatidyl inositol anchor. Whereas PrPC is highly expressed in the central nervous system (CNS), Dpl is detected mostly in testes and its ectopic expression in the CNS leads to ataxia as well as Purkinje and granule cell degeneration in the cerebellum. The mechanism through which Dpl induces neurotoxicity is still debated. In the present work, primary neuronal cultures derived from postnatal cerebellar granule cells of wild-type and PrP-knockout FVB mice were used in order to investigate the molecular events that occur upon exposure to Dpl. Treatment of cultured cerebellar neurons with recombinant Dpl produced apoptosis that could be prevented by PrP co-incubation. When primary neuronal cultures from Bax-deficient mice were incubated with Dpl, no apoptosis was observed, suggesting an important role of Bax in triggering neurodegeneration. Similarly, cell survival increased when recDpl-treated cells were incubated with an inhibitor of caspase-3, which mediates apoptosis in mammalian cells. Together, our findings raise the possibility that Bax and caspase-3 feature in Dpl-mediated apoptosis.

show abstract

Doppel induces autophagic stress in prion protein-deficient Purkinje cells

Cited by 11 publications

References 13 publications

Activation of the macroautophagic system in scrapie-infected experimental animals and human genetic prion diseases

Activation of the macroautophagic system in scrapie-infected experimental animals and human genetic prion diseases

Role of autophagy in prion protein-induced neurodegenerative diseases

The role of Bax and caspase-3 in doppel-induced apoptosis of cerebellar granule cells

Contact Info

Product

Resources

About