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| Home > Publications Database > Mitochondrial complex 1 inhibition increases 4-repeat isoform tau by SRSF2 upregulation. |
| Home > Publications Database > Mitochondrial complex 1 inhibition increases 4-repeat isoform tau by SRSF2 upregulation. |
| Journal Article | DZNE-2020-03961 |
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2014
PLOS
San Francisco, California, US
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Please use a persistent id in citations: doi:10.1371/journal.pone.0113070
Abstract: 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.
Keyword(s): Alternative Splicing (MeSH) ; Electron Transport Complex I: antagonists & inhibitors (MeSH) ; Electron Transport Complex I: metabolism (MeSH) ; Female (MeSH) ; Furans: pharmacology (MeSH) ; Gene Expression Regulation: drug effects (MeSH) ; Humans (MeSH) ; Lactones: pharmacology (MeSH) ; Nuclear Proteins: metabolism (MeSH) ; Oxidative Stress (MeSH) ; Protein Interaction Domains and Motifs (MeSH) ; RNA Isoforms (MeSH) ; Ribonucleoproteins: metabolism (MeSH) ; Serine-Arginine Splicing Factors (MeSH) ; Supranuclear Palsy, Progressive: genetics (MeSH) ; Supranuclear Palsy, Progressive: metabolism (MeSH) ; Up-Regulation (MeSH) ; tau Proteins: chemistry (MeSH) ; tau Proteins: genetics (MeSH) ; tau Proteins: metabolism (MeSH) ; Furans ; Lactones ; Nuclear Proteins ; RNA Isoforms ; Ribonucleoproteins ; tau Proteins ; SRSF2 protein, human ; Serine-Arginine Splicing Factors ; annonacin ; Electron Transport Complex I
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