000140674 001__ 140674
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000140674 0247_ $$2doi$$a10.1016/j.jmb.2019.01.034
000140674 0247_ $$2pmid$$apmid:30711541
000140674 0247_ $$2ISSN$$a0022-2836
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000140674 037__ $$aDZNE-2020-06996
000140674 041__ $$aEnglish
000140674 082__ $$a610
000140674 1001_ $$0P:(DE-2719)2810643$$aSchilling, Judith$$b0$$eFirst author$$udzne
000140674 245__ $$aDeregulated Splicing Is a Major Mechanism of RNA-Induced Toxicity in Huntington's Disease.
000140674 260__ $$aAmsterdam [u.a.]$$bElsevier$$c2019
000140674 264_1 $$2Crossref$$3print$$bElsevier BV$$c2019-04-01
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000140674 520__ $$aHuntington's disease (HD) is caused by an expanded CAG repeat in the huntingtin (HTT) gene, translating into an elongated polyglutamine stretch. In addition to the neurotoxic mutant HTT protein, the mutant CAG repeat RNA can exert toxic functions by trapping RNA-binding proteins. While few examples of proteins that aberrantly bind to mutant HTT RNA and execute abnormal function in conjunction with the CAG repeat RNA have been described, an unbiased approach to identify the interactome of mutant HTT RNA is missing. Here, we describe the analysis of proteins that preferentially bind mutant HTT RNA using a mass spectrometry approach. We show that (I) the majority of proteins captured by mutant HTT RNA belong to the spliceosome pathway, (II) expression of mutant CAG repeat RNA induces mis-splicing in a HD cell model, (III) overexpression of one of the splice factors trapped by mutant HTT ameliorates the HD phenotype in a fly model and (VI) deregulated splicing occurs in human HD brain. Our data suggest that deregulated splicing is a prominent mechanism of RNA-induced toxicity in HD.
000140674 536__ $$0G:(DE-HGF)POF3-342$$a342 - Disease Mechanisms and Model Systems (POF3-342)$$cPOF3-342$$fPOF III$$x0
000140674 536__ $$0G:(DE-HGF)POF3-341$$a341 - Molecular Signaling (POF3-341)$$cPOF3-341$$fPOF III$$x1
000140674 542__ $$2Crossref$$i2019-04-01$$uhttps://www.elsevier.com/tdm/userlicense/1.0/
000140674 542__ $$2Crossref$$i2019-02-02$$uhttp://creativecommons.org/licenses/by-nc-nd/4.0/
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000140674 650_2 $$2MeSH$$aAnimals
000140674 650_2 $$2MeSH$$aHumans
000140674 650_2 $$2MeSH$$aHuntingtin Protein: genetics
000140674 650_2 $$2MeSH$$aHuntington Disease: genetics
000140674 650_2 $$2MeSH$$aRNA: genetics
000140674 650_2 $$2MeSH$$aRNA Splicing: genetics
000140674 650_2 $$2MeSH$$aSpliceosomes: genetics
000140674 7001_ $$0P:(DE-2719)2810307$$aBroemer, Meike$$b1$$udzne
000140674 7001_ $$aAtanassov, Ilian$$b2
000140674 7001_ $$0P:(DE-2719)2810519$$aDürnberger, Yvonne$$b3$$udzne
000140674 7001_ $$0P:(DE-2719)2481765$$aVorberg, Ina$$b4$$udzne
000140674 7001_ $$aDieterich, Christoph$$b5
000140674 7001_ $$aDagane, Alina$$b6
000140674 7001_ $$aDittmar, Gunnar$$b7
000140674 7001_ $$aWanker, Erich$$b8
000140674 7001_ $$avan Roon-Mom, Willeke$$b9
000140674 7001_ $$aWinter, Jennifer$$b10
000140674 7001_ $$0P:(DE-2719)2421562$$aKrauß, Sybille$$b11$$eLast author$$udzne
000140674 77318 $$2Crossref$$3journal-article$$a10.1016/j.jmb.2019.01.034$$b : Elsevier BV, 2019-04-01$$n9$$p1869-1877$$tJournal of Molecular Biology$$v431$$x0022-2836$$y2019
000140674 773__ $$0PERI:(DE-600)1355192-9$$a10.1016/j.jmb.2019.01.034$$gVol. 431, no. 9, p. 1869 - 1877$$n9$$p1869-1877$$q431:9<1869 - 1877$$tJournal of molecular biology$$v431$$x0022-2836$$y2019
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000140674 9201_ $$0I:(DE-2719)1011006$$kAG Krauß ; AG Krauß$$lRegulatory RNA-protein interaction in neurodegenerative diseases$$x0
000140674 9201_ $$0I:(DE-2719)5000021$$kAG Brömer 1 ; AG Brömer 1$$lUbiquitin-Mediated Processes in Neurodegenerative Diseases$$x1
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