Source:http://linkedlifedata.com/resource/pubmed/id/16723374
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Predicate | Object |
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rdf:type | |
lifeskim:mentions | |
pubmed:issue |
13
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pubmed:dateCreated |
2006-6-22
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pubmed:abstractText |
Myotonic dystrophy type 1 (DM1) is a neuromuscular disorder caused by a CTG expansion in the 3' UTR of the dystrophia myotonica protein kinase (DMPK) gene. It has been hypothesized that the pathogenesis in DM1 is triggered by a toxic gain of function of the expanded DMPK RNA. This expanded RNA is retained in nuclear foci where it sequesters and induces alterations in the levels of RNA-binding proteins (RNA-BP). To model DM1 and study the implication of RNA-BP in CUG-induced toxicity, we have generated a Drosophila DM1 model expressing a non-coding mRNA containing 480 interrupted CUG repeats; i.e. [(CUG)20CUCGA]24. This (iCUG)480 transcript accumulates in nuclear foci and its expression leads to muscle wasting and degeneration in Drosophila. We also report that altering the levels of two RNA-BP known to be involved in DM1 pathogenesis, MBNL1 and CUGBP1, modify the (iCUG)480 degenerative phenotypes. Expanded CUG-induced toxicity in Drosophila is suppressed when MBNL1 expression levels are increased, and enhanced when MBNL1 levels are reduced. In addition, (iCUG)480 also causes a decrease in the levels of soluble MBNL1 that is sequestered in the CUG-containing nuclear foci. In contrast, increasing the levels of CUGBP1 worsens (iCUG)480-induced degeneration even though CUGBP1 distribution is not altered by the expression of the expanded triplet repeat. Our data supports a mechanism for DM1 pathogenesis in which decreased levels of MBNL and increased levels of CUGBP mediate the RNA-induced toxicity observed in DM1. Perhaps more importantly, they also provide proof of the principle that CUG-induced muscle toxicity can be suppressed.
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pubmed:grant | |
pubmed:language |
eng
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pubmed:journal | |
pubmed:citationSubset |
IM
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pubmed:chemical | |
pubmed:status |
MEDLINE
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pubmed:month |
Jul
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pubmed:issn |
0964-6906
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pubmed:author | |
pubmed:issnType |
Print
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pubmed:day |
1
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pubmed:volume |
15
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
2138-45
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pubmed:dateRevised |
2010-9-16
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pubmed:meshHeading |
pubmed-meshheading:16723374-Animals,
pubmed-meshheading:16723374-Animals, Genetically Modified,
pubmed-meshheading:16723374-Blotting, Northern,
pubmed-meshheading:16723374-Cell Nucleus,
pubmed-meshheading:16723374-Disease Models, Animal,
pubmed-meshheading:16723374-Drosophila melanogaster,
pubmed-meshheading:16723374-Eye,
pubmed-meshheading:16723374-Humans,
pubmed-meshheading:16723374-In Situ Hybridization,
pubmed-meshheading:16723374-Microscopy, Electron, Scanning,
pubmed-meshheading:16723374-Muscles,
pubmed-meshheading:16723374-Myotonic Dystrophy,
pubmed-meshheading:16723374-RNA, Messenger,
pubmed-meshheading:16723374-RNA-Binding Proteins,
pubmed-meshheading:16723374-Trinucleotide Repeat Expansion
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pubmed:year |
2006
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pubmed:articleTitle |
MBNL1 and CUGBP1 modify expanded CUG-induced toxicity in a Drosophila model of myotonic dystrophy type 1.
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pubmed:affiliation |
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't,
Research Support, N.I.H., Extramural
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