Analysis of doppel protein toxicity

Cui, Tingru; Holme, Andrea L.; Sassoon, Judyth; Brown, David R.

doi:10.1016/s1044-7431(03)00017-4

Cited by 41 publications

(45 citation statements)

References 42 publications

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“…In our genetic analyses, the region including residues 101-125 can exert a pro-apoptotic effect in the absence of ␣A or ␣C (Fig. 6), but it is unclear whether residues 101-125 in solution adopt an interrupted helical conformation in the absence of other portions of the protein; for example, in the NMR structure the kinked region involves a hydrogen bond between Asn-117 and Phe-60 in the first ␤-strand (15), and a synthetic peptide corresponding to the helix B region assessed in phosphate buffer was characterized by a random coil signature (55). The interval defined by the 101-125-residue deletion has also attracted prior interest as overlapping a Cu(II)-binding site defined by fluorescence quenching, equilibrium dialysis binding, and mass spectrometric analysis of a Dpl-(101-145) peptide (18).…”

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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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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“…Deregulation of this balance may lead to neuropathology. 9,10 In humans, several polymorphisms have been described in PRND. However, findings on the association of these polymorphisms with CJD are inconsistent.…”

Section: Introductionmentioning

confidence: 99%

Polymorphisms in the prion protein gene and in the doppel gene increase susceptibility for Creutzfeldt–Jakob disease

et al. 2004

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The prion protein gene (PRNP) plays a central role in the origin of Creutzfeldt-Jakob disease (CJD), but there is growing interest in other polymorphisms that may be involved in CJD. Polymorphisms upstream of PRNP that may modulate the prion protein production as well as polymorphisms in the prion-like doppel gene (PRND) have been studied, with inconsistent findings. We investigated the role of a single-nucleotide polymorphism (SNP 1368) located upstream of PRNP and three polymorphisms in PRND (T26M, P56L and T174M) in CJD. The study included a population-based sample of 52 patients with sporadic CJD and 250 controls. We analysed our data as single markers and haplotypes. Further, we conducted a meta-analysis on PRND T174M comparing the data of the four studies conducted to date. For SNP 1368 and PRNP M129V, we found significant evidence for linkage disequilibrium. No evidence was found for a relation of SNP 1368 to CJD independent of PRNP M129V. We further found a significant increased prevalence of M homozygotes at PRND T174M among sporadic CJD patients, when adjusting the analyses for the other genotypes. In the haplotype analyses, the association was strongest for persons homozygous for PRNP 129M and PRND 174M (odds ratio 4.35, 95% confidence interval 1.05 -8.09; P ¼ 0.04). The meta-analysis on the PRND T174M polymorphism did not show a consistent effect across studies, raising the question as to whether PRND 174M is causally related to CJD, or whether the PRND allele is in linkage disequilibrium with another polymorphism related to CJD.

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“…Interestingly, it was shown that enzymatic activity of superoxide dismutase, a superoxidedetoxifying enzyme, was significantly decreased in PrP-/-mice (18). Moreover, it was reported that recombinant PrPLP/Dpl was toxic to the cultured cerebellar neurons of non-ataxic Zrch I PrP-/-mice and that this PrPLP/Dpl-neurotoxicity could be prevented by L-N -acetyl methyl ester, a pharmacological inhibitor of NO synthases (49). It is therefore possible that PrPLP/Dpl might aggravate oxidative stress by overproducing NO and superoxide, thereby causing Purkinje cell death, and that PrP C could detoxify it, preventing PrPLP/Dpl-induced neurodegeneration.…”

Section: Antagonistic Signals Of Prp and Prplp/dpl In Neuronal Cell Dmentioning

confidence: 99%

Molecular biology of prion protein and its first homologous protein

Sakaguchi

2007

J. Med. Invest.

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Analysis of doppel protein toxicity

Cited by 41 publications

References 42 publications

Genetic Mapping of Activity Determinants within Cellular Prion Proteins

Genetic Mapping of Activity Determinants within Cellular Prion Proteins

Polymorphisms in the prion protein gene and in the doppel gene increase susceptibility for Creutzfeldt–Jakob disease

Molecular biology of prion protein and its first homologous protein

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