|
rdf:type |
|
|
lifeskim:mentions |
|
|
pubmed:issue |
53
|
|
pubmed:dateCreated |
2004-12-23
|
|
pubmed:abstractText |
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 PrPDelta32-121 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 PrPDelta132-121 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 (PrPDelta23-28), by deletion of all five octarepeats (PrPDelta51-90), 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' (DplDelta101-125). 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.
|
|
pubmed:language |
eng
|
|
pubmed:journal |
|
|
pubmed:citationSubset |
IM
|
|
pubmed:chemical |
|
|
pubmed:status |
MEDLINE
|
|
pubmed:month |
Dec
|
|
pubmed:issn |
0021-9258
|
|
pubmed:author |
pubmed-author:AhrensRosemaryR,
pubmed-author:ChishtiM AzharMA,
pubmed-author:CoomaraswamyJanakyJ,
pubmed-author:DrisaldiBettinaB,
pubmed-author:FraserPaul EPE,
pubmed-author:KretzschmarHansH,
pubmed-author:MajorFrançoisF,
pubmed-author:MarviMelissaM,
pubmed-author:MastrangeloPeterP,
pubmed-author:MountHoward T JHT,
pubmed-author:StromeBobB,
pubmed-author:SyMan-SunMS,
pubmed-author:WattsJoel CJC,
pubmed-author:WestawayDavidD,
pubmed-author:WindlOttoO,
pubmed-author:YangJingJ
|
|
pubmed:issnType |
Print
|
|
pubmed:day |
31
|
|
pubmed:volume |
279
|
|
pubmed:owner |
NLM
|
|
pubmed:authorsComplete |
Y
|
|
pubmed:pagination |
55443-54
|
|
pubmed:dateRevised |
2010-11-18
|
|
pubmed:meshHeading |
pubmed-meshheading:15459186-Alleles,
pubmed-meshheading:15459186-Animals,
pubmed-meshheading:15459186-Apoptosis,
pubmed-meshheading:15459186-Cell Death,
pubmed-meshheading:15459186-Cell Line, Tumor,
pubmed-meshheading:15459186-Cerebellum,
pubmed-meshheading:15459186-Chromosome Mapping,
pubmed-meshheading:15459186-Copper,
pubmed-meshheading:15459186-DNA Mutational Analysis,
pubmed-meshheading:15459186-Endocytosis,
pubmed-meshheading:15459186-GPI-Linked Proteins,
pubmed-meshheading:15459186-Gene Deletion,
pubmed-meshheading:15459186-Glycine,
pubmed-meshheading:15459186-Green Fluorescent Proteins,
pubmed-meshheading:15459186-Ions,
pubmed-meshheading:15459186-Mice,
pubmed-meshheading:15459186-Mice, Transgenic,
pubmed-meshheading:15459186-Microscopy, Fluorescence,
pubmed-meshheading:15459186-Models, Genetic,
pubmed-meshheading:15459186-Mutation,
pubmed-meshheading:15459186-Neurons,
pubmed-meshheading:15459186-Phenotype,
pubmed-meshheading:15459186-Plasmids,
pubmed-meshheading:15459186-Point Mutation,
pubmed-meshheading:15459186-PrPC Proteins,
pubmed-meshheading:15459186-Prions,
pubmed-meshheading:15459186-Protein Binding,
pubmed-meshheading:15459186-Protein Structure, Tertiary,
pubmed-meshheading:15459186-Transfection,
pubmed-meshheading:15459186-Transgenes
|
|
pubmed:year |
2004
|
|
pubmed:articleTitle |
Genetic mapping of activity determinants within cellular prion proteins: N-terminal modules in PrPC offset pro-apoptotic activity of the Doppel helix B/B' region.
|
|
pubmed:affiliation |
Centre for Research in Neurodegenerative Diseases, Tanz Neuroscience Building, 6 Queen's Park Crescent West, University of Toronto, Toronto, Ontario M5S 3H2, Canada.
|
|
pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
|
