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000137639 0247_ $$2doi$$a10.1371/journal.pone.0113070
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000137639 1001_ $$0P:(DE-2719)2810685$$aBruch, Julius$$b0$$eFirst author$$udzne
000137639 245__ $$aMitochondrial complex 1 inhibition increases 4-repeat isoform tau by SRSF2 upregulation.
000137639 260__ $$aSan Francisco, California, US$$bPLOS$$c2014
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000137639 520__ $$aProgressive Supranuclear Palsy (PSP) is a neurodegenerative disorder characterised by intracellular aggregation of the microtubule-associated protein tau. The tau protein exists in 6 predominant isoforms. Depending on alternative splicing of exon 10, three of these isoforms have four microtubule-binding repeat domains (4R), whilst the others only have three (3R). In PSP there is an excess of the 4R tau isoforms, which are thought to contribute significantly to the pathological process. The cause of this 4R increase is so far unknown. Several lines of evidence link mitochondrial complex I inhibition to the pathogenesis of PSP. We demonstrate here for the first time that annonacin and MPP(+), two prototypical mitochondrial complex I inhibitors, increase the 4R isoforms of tau in human neurons. We show that the splicing factor SRSF2 is necessary to increase 4R tau with complex I inhibition. We also found SRSF2, as well as another tau splicing factor, TRA2B, to be increased in brains of PSP patients. Thereby, we provide new evidence that mitochondrial complex I inhibition may contribute as an upstream event to the pathogenesis of PSP and suggest that splicing factors may represent an attractive therapeutic target to intervene in the disease process.
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000137639 542__ $$2Crossref$$i2014-11-17$$uhttp://creativecommons.org/licenses/by/4.0/
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000137639 650_7 $$2NLM Chemicals$$aFurans
000137639 650_7 $$2NLM Chemicals$$aLactones
000137639 650_7 $$2NLM Chemicals$$aNuclear Proteins
000137639 650_7 $$2NLM Chemicals$$aRNA Isoforms
000137639 650_7 $$2NLM Chemicals$$aRibonucleoproteins
000137639 650_7 $$2NLM Chemicals$$atau Proteins
000137639 650_7 $$0147153-65-9$$2NLM Chemicals$$aSRSF2 protein, human
000137639 650_7 $$0170974-22-8$$2NLM Chemicals$$aSerine-Arginine Splicing Factors
000137639 650_7 $$040372ET6TM$$2NLM Chemicals$$aannonacin
000137639 650_7 $$0EC 7.1.1.2$$2NLM Chemicals$$aElectron Transport Complex I
000137639 650_2 $$2MeSH$$aAlternative Splicing
000137639 650_2 $$2MeSH$$aElectron Transport Complex I: antagonists & inhibitors
000137639 650_2 $$2MeSH$$aElectron Transport Complex I: metabolism
000137639 650_2 $$2MeSH$$aFemale
000137639 650_2 $$2MeSH$$aFurans: pharmacology
000137639 650_2 $$2MeSH$$aGene Expression Regulation: drug effects
000137639 650_2 $$2MeSH$$aHumans
000137639 650_2 $$2MeSH$$aLactones: pharmacology
000137639 650_2 $$2MeSH$$aNuclear Proteins: metabolism
000137639 650_2 $$2MeSH$$aOxidative Stress
000137639 650_2 $$2MeSH$$aProtein Interaction Domains and Motifs
000137639 650_2 $$2MeSH$$aRNA Isoforms
000137639 650_2 $$2MeSH$$aRibonucleoproteins: metabolism
000137639 650_2 $$2MeSH$$aSerine-Arginine Splicing Factors
000137639 650_2 $$2MeSH$$aSupranuclear Palsy, Progressive: genetics
000137639 650_2 $$2MeSH$$aSupranuclear Palsy, Progressive: metabolism
000137639 650_2 $$2MeSH$$aUp-Regulation
000137639 650_2 $$2MeSH$$atau Proteins: chemistry
000137639 650_2 $$2MeSH$$atau Proteins: genetics
000137639 650_2 $$2MeSH$$atau Proteins: metabolism
000137639 7001_ $$0P:(DE-2719)2810884$$aXu, Hong$$b1$$udzne
000137639 7001_ $$0P:(DE-2719)2813101$$aDe Andrade, Anderson$$b2$$udzne
000137639 7001_ $$0P:(DE-2719)2811373$$aHöglinger, Günter$$b3$$eLast author$$udzne
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