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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
19
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pubmed:dateCreated |
2008-5-5
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pubmed:abstractText |
TAR DNA-binding protein 43 (TDP-43) is the disease protein in frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) and amyotrophic lateral sclerosis (ALS). Although normal TDP-43 is a nuclear protein, pathological TDP-43 is redistributed and sequestered as insoluble aggregates in neuronal nuclei, perikarya, and neurites. Here we recapitulate these pathological phenotypes in cultured cells by altering endogenous TDP-43 nuclear trafficking and by expressing mutants with defective nuclear localization (TDP-43-DeltaNLS) or nuclear export signals (TDP-43-DeltaNES). Restricting endogenous cytoplasmic TDP-43 from entering the nucleus or preventing its exit out of the nucleus resulted in TDP-43 aggregate formation. TDP-43-DeltaNLS accumulates as insoluble cytoplasmic aggregates and sequesters endogenous TDP-43, thereby depleting normal nuclear TDP-43, whereas TDP-43-DeltaNES forms insoluble nuclear aggregates with endogenous TDP-43. Mutant forms of TDP-43 also replicate the biochemical profile of pathological TDP-43 in FTLD-U/ALS. Thus, FTLD-U/ALS pathogenesis may be linked mechanistically to deleterious perturbations of nuclear trafficking and solubility of TDP-43.
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pubmed:grant |
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pubmed:commentsCorrections |
http://linkedlifedata.com/resource/pubmed/commentcorrection/18305110-11708987,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18305110-12030310,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18305110-14667816,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18305110-15654337,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18305110-15826655,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18305110-1692628,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18305110-17003490,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18305110-17023659,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18305110-17084815,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18305110-17219193,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18305110-17333220,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18305110-17356379,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18305110-17360763,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18305110-17469116,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18305110-17591968,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18305110-3276076,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18305110-3678831,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18305110-6209285,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18305110-9334337,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18305110-9683540,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18305110-9855500
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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 |
May
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pubmed:issn |
0021-9258
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:day |
9
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pubmed:volume |
283
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
13302-9
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pubmed:dateRevised |
2009-11-18
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pubmed:meshHeading |
pubmed-meshheading:18305110-Animals,
pubmed-meshheading:18305110-Cell Line,
pubmed-meshheading:18305110-Cell Nucleus,
pubmed-meshheading:18305110-Cytoplasm,
pubmed-meshheading:18305110-DNA-Binding Proteins,
pubmed-meshheading:18305110-Disease,
pubmed-meshheading:18305110-Gene Expression Regulation,
pubmed-meshheading:18305110-Humans,
pubmed-meshheading:18305110-Mice,
pubmed-meshheading:18305110-Molecular Sequence Data,
pubmed-meshheading:18305110-Mutation,
pubmed-meshheading:18305110-Nuclear Localization Signals,
pubmed-meshheading:18305110-Ubiquitination
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pubmed:year |
2008
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pubmed:articleTitle |
Disturbance of nuclear and cytoplasmic TAR DNA-binding protein (TDP-43) induces disease-like redistribution, sequestration, and aggregate formation.
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pubmed:affiliation |
Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
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pubmed:publicationType |
Journal Article,
Research Support, N.I.H., Extramural
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