Prion and doppel proteins bind to granule cells of the cerebellum

Legname, Giuseppe; Nelken, Peter; Guan, Zhengyu; Kanyo, Z.F.; DeArmond, Stephen J.; Prusiner, Stanley B.

doi:10.1073/pnas.242611999

Cited by 24 publications

(27 citation statements)

References 55 publications

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“…According to our ELISA data, Dpl binds to PrP and this interaction has been recently confirmed either by SPR or by in vivo experiments 33 , 38 . Moreover, Dpl has been shown to interact distinctively with a plasma metalloproteinase inhibitor, the α-2-macroblobulin (α 2 M), in the granule cell layer of the cerebellum 32 , 33 . According to the proposed mechanism, in the absence of PrP, Dpl could bind and sequester α 2 M and the withdrawal of proteinase inhibitors may eventually lead to cerebellar degeneration.…”

Section: Discussionsupporting

confidence: 56%

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

Didonna

Sussman

Benetti

et al. 2012

Prion

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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.

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Section: Discussionsupporting

confidence: 56%

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

Didonna

Sussman

Benetti

et al. 2012

Prion

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“…In this regard, histoblots have revealed that either Fc-labelled Dpl or PrP c bind specifically to cerebellar granule neurons (CGNs) (Legname et al, 2002), which may explain why the cerebellum suffers degeneration in Dpl-mediated degeneration while other brain structures remain healthy.…”

Section: Other Prp C Mutant Mice: the Puzzle Of Functions Increasesmentioning

confidence: 99%

New insights into cellular prion protein (PrPc) functions: The “ying and yang” of a relevant protein

Nicolas

Gavı́n

Rı́o

2009

Brain Research Reviews

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“…forms of Prnp,"⌬PrP") have traditionally been equated with protein activities (24,25,72), because unusual secondary structures have been proposed for Prnp mRNA (73)(74)(75) and conversion of PrP C to protease-resistant forms is facilitated by cellular RNAs (76,77), we also considered RNA-based mechanisms. To exclude biological properties of this ribonucleotide sequence as a basis for pro-apoptotic activity, we created a Prnd allele with tandem stop codons inserted just upstream of this position (Dpl91,92terter).…”

Section: Activity Determinants In Prp C and Dplmentioning

confidence: 99%

Genetic Mapping of Activity Determinants within Cellular Prion Proteins

Drisaldi

Coomaraswamy

Mastrangelo

et al. 2004

Journal of Biological Chemistry

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The PrP-like Doppel (Dpl) protein causes apoptotic death of cerebellar neurons in transgenic mice, a process prevented by expression of the wild type (wt) cellular prion protein, PrP C . Internally deleted forms of PrP C resembling Dpl such as PrP⌬32-121 produce a similar PrP C -sensitive pro-apoptotic phenotype in transgenic mice. Here we demonstrate that these phenotypic attributes of wt Dpl, wt PrP C , and PrP⌬132-121 can be accurately recapitulated by transfected mouse cerebellar granule cell cultures. This system was then explored by mutagenesis of the co-expressed prion proteins to reveal functional determinants. By this means, neuroprotective activity of wt PrP C was shown to be nullified by a deletion of the N-terminal charged region implicated in endocytosis and retrograde axonal transport (PrP⌬23-28), by deletion of all five octarepeats (PrP⌬51-90), or by glycine replacement of four octarepeat histidine residues required for selective binding of copper ions (Prnp"H/G"). In the case of Dpl, overlapping deletions defined a requirement for the gene interval encoding helices B and B (Dpl⌬101-125). These data suggest contributions of copper binding and neuronal trafficking to wt PrP C function in vivo and place constraints upon current hypotheses to explain Dpl/PrP C antagonism by competitive ligand binding. Further implementation of this assay should provide a fuller understanding of the attributes and subcellular localizations required for activity of these enigmatic proteins.

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Prion and doppel proteins bind to granule cells of the cerebellum

Cited by 24 publications

References 55 publications

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

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

New insights into cellular prion protein (PrPc) functions: The “ying and yang” of a relevant protein

Genetic Mapping of Activity Determinants within Cellular Prion Proteins

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