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rdf:type |
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lifeskim:mentions |
umls-concept:C0002345,
umls-concept:C0008659,
umls-concept:C0208973,
umls-concept:C0242422,
umls-concept:C0338451,
umls-concept:C1517892,
umls-concept:C1704666,
umls-concept:C1720655,
umls-concept:C1947974,
umls-concept:C1947976,
umls-concept:C2700455
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pubmed:issue |
46
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|
pubmed:dateCreated |
2001-11-12
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|
pubmed:abstractText |
Mutations in the human tau gene cause frontotemporal dementia and Parkinsonism associated with chromosome 17 (FTDP-17). One of the major disease mechanisms in FTDP-17 is the increased inclusion of tau exon 10 during pre-mRNA splicing. Here we show that modified oligonucleotides directed against the tau exon 10 splice junctions suppress inclusion of tau exon 10. The effect is mediated by the formation of a stable pre-mRNA-oligonucleotide hybrid, which blocks access of the splicing machinery to the pre-mRNA. Correction of tau splicing occurs in a tau minigene system and in endogenous tau RNA in neuronal pheochromocytoma cells and is specific to exon 10 of the tau gene. Antisense oligonucleotide-mediated exclusion of exon 10 has a physiological effect by increasing the ratio of protein lacking the microtubule-binding domain encoded by exon 10. As a consequence, the microtubule cytoskeleton becomes destabilized and cell morphology is altered. Our results demonstrate that alternative splicing defects of tau as found in FTDP-17 patients can be corrected by application of antisense oligonucleotides. These findings provide a tool to study specific tau isoforms in vivo and might lead to a novel therapeutic strategy for FTDP-17.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
Nov
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pubmed:issn |
0021-9258
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pubmed:author |
|
|
pubmed:issnType |
Print
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pubmed:day |
16
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pubmed:volume |
276
|
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pubmed:owner |
NLM
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|
pubmed:authorsComplete |
Y
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pubmed:pagination |
42986-93
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pubmed:dateRevised |
2004-11-17
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pubmed:meshHeading |
pubmed-meshheading:11560926-Alternative Splicing,
pubmed-meshheading:11560926-Animals,
pubmed-meshheading:11560926-Base Sequence,
pubmed-meshheading:11560926-Blotting, Western,
pubmed-meshheading:11560926-COS Cells,
pubmed-meshheading:11560926-Cell Line,
pubmed-meshheading:11560926-Chromosomes, Human, Pair 17,
pubmed-meshheading:11560926-Cytoskeleton,
pubmed-meshheading:11560926-Dementia,
pubmed-meshheading:11560926-Dose-Response Relationship, Drug,
pubmed-meshheading:11560926-Exons,
pubmed-meshheading:11560926-Humans,
pubmed-meshheading:11560926-Microscopy, Fluorescence,
pubmed-meshheading:11560926-Molecular Sequence Data,
pubmed-meshheading:11560926-Mutation,
pubmed-meshheading:11560926-Neurons,
pubmed-meshheading:11560926-Oligonucleotides,
pubmed-meshheading:11560926-Oligonucleotides, Antisense,
pubmed-meshheading:11560926-PC12 Cells,
pubmed-meshheading:11560926-Parkinson Disease,
pubmed-meshheading:11560926-Point Mutation,
pubmed-meshheading:11560926-Protein Structure, Tertiary,
pubmed-meshheading:11560926-RNA,
pubmed-meshheading:11560926-RNA, Messenger,
pubmed-meshheading:11560926-Rats,
pubmed-meshheading:11560926-Reverse Transcriptase Polymerase Chain Reaction,
pubmed-meshheading:11560926-Transfection,
pubmed-meshheading:11560926-tau Proteins
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pubmed:year |
2001
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|
pubmed:articleTitle |
Correction of alternative splicing of tau in frontotemporal dementia and parkinsonism linked to chromosome 17.
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pubmed:affiliation |
National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
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pubmed:publicationType |
Journal Article
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