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024 7 _ |a 10.1371/journal.pone.0113070
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024 7 _ |a pmc:PMC4234644
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037 _ _ |a DZNE-2020-03961
041 _ _ |a English
082 _ _ |a 610
100 1 _ |a Bruch, Julius
|0 P:(DE-2719)2810685
|b 0
|e First author
|u dzne
245 _ _ |a Mitochondrial complex 1 inhibition increases 4-repeat isoform tau by SRSF2 upregulation.
260 _ _ |a San Francisco, California, US
|c 2014
|b PLOS
264 _ 1 |3 online
|2 Crossref
|b Public Library of Science (PLoS)
|c 2014-11-17
336 7 _ |a article
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336 7 _ |a ARTICLE
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336 7 _ |a Journal Article
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520 _ _ |a Progressive 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.
536 _ _ |a 344 - Clinical and Health Care Research (POF3-344)
|0 G:(DE-HGF)POF3-344
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|f POF III
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542 _ _ |i 2014-11-17
|2 Crossref
|u http://creativecommons.org/licenses/by/4.0/
588 _ _ |a Dataset connected to CrossRef, PubMed,
650 _ 7 |a Furans
|2 NLM Chemicals
650 _ 7 |a Lactones
|2 NLM Chemicals
650 _ 7 |a Nuclear Proteins
|2 NLM Chemicals
650 _ 7 |a RNA Isoforms
|2 NLM Chemicals
650 _ 7 |a Ribonucleoproteins
|2 NLM Chemicals
650 _ 7 |a tau Proteins
|2 NLM Chemicals
650 _ 7 |a SRSF2 protein, human
|0 147153-65-9
|2 NLM Chemicals
650 _ 7 |a Serine-Arginine Splicing Factors
|0 170974-22-8
|2 NLM Chemicals
650 _ 7 |a annonacin
|0 40372ET6TM
|2 NLM Chemicals
650 _ 7 |a Electron Transport Complex I
|0 EC 7.1.1.2
|2 NLM Chemicals
650 _ 2 |a Alternative Splicing
|2 MeSH
650 _ 2 |a Electron Transport Complex I: antagonists & inhibitors
|2 MeSH
650 _ 2 |a Electron Transport Complex I: metabolism
|2 MeSH
650 _ 2 |a Female
|2 MeSH
650 _ 2 |a Furans: pharmacology
|2 MeSH
650 _ 2 |a Gene Expression Regulation: drug effects
|2 MeSH
650 _ 2 |a Humans
|2 MeSH
650 _ 2 |a Lactones: pharmacology
|2 MeSH
650 _ 2 |a Nuclear Proteins: metabolism
|2 MeSH
650 _ 2 |a Oxidative Stress
|2 MeSH
650 _ 2 |a Protein Interaction Domains and Motifs
|2 MeSH
650 _ 2 |a RNA Isoforms
|2 MeSH
650 _ 2 |a Ribonucleoproteins: metabolism
|2 MeSH
650 _ 2 |a Serine-Arginine Splicing Factors
|2 MeSH
650 _ 2 |a Supranuclear Palsy, Progressive: genetics
|2 MeSH
650 _ 2 |a Supranuclear Palsy, Progressive: metabolism
|2 MeSH
650 _ 2 |a Up-Regulation
|2 MeSH
650 _ 2 |a tau Proteins: chemistry
|2 MeSH
650 _ 2 |a tau Proteins: genetics
|2 MeSH
650 _ 2 |a tau Proteins: metabolism
|2 MeSH
700 1 _ |a Xu, Hong
|0 P:(DE-2719)2810884
|b 1
|u dzne
700 1 _ |a De Andrade, Anderson
|0 P:(DE-2719)2813101
|b 2
|u dzne
700 1 _ |a Höglinger, Günter
|0 P:(DE-2719)2811373
|b 3
|e Last author
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773 1 8 |a 10.1371/journal.pone.0113070
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773 _ _ |a 10.1371/journal.pone.0113070
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910 1 _ |a Deutsches Zentrum für Neurodegenerative Erkrankungen
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913 1 _ |a DE-HGF
|b Forschungsbereich Gesundheit
|l Erkrankungen des Nervensystems
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