TY  - JOUR
AU  - Bruch, Julius
AU  - Xu, Hong
AU  - De Andrade, Anderson
AU  - Höglinger, Günter
TI  - Mitochondrial complex 1 inhibition increases 4-repeat isoform tau by SRSF2 upregulation.
JO  - PLOS ONE
VL  - 9
IS  - 11
SN  - 1932-6203
CY  - San Francisco, California, US
PB  - PLOS
M1  - DZNE-2020-03961
SP  - e113070
PY  - 2014
AB  - 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.
KW  - Alternative Splicing
KW  - Electron Transport Complex I: antagonists & inhibitors
KW  - Electron Transport Complex I: metabolism
KW  - Female
KW  - Furans: pharmacology
KW  - Gene Expression Regulation: drug effects
KW  - Humans
KW  - Lactones: pharmacology
KW  - Nuclear Proteins: metabolism
KW  - Oxidative Stress
KW  - Protein Interaction Domains and Motifs
KW  - RNA Isoforms
KW  - Ribonucleoproteins: metabolism
KW  - Serine-Arginine Splicing Factors
KW  - Supranuclear Palsy, Progressive: genetics
KW  - Supranuclear Palsy, Progressive: metabolism
KW  - Up-Regulation
KW  - tau Proteins: chemistry
KW  - tau Proteins: genetics
KW  - tau Proteins: metabolism
KW  - Furans (NLM Chemicals)
KW  - Lactones (NLM Chemicals)
KW  - Nuclear Proteins (NLM Chemicals)
KW  - RNA Isoforms (NLM Chemicals)
KW  - Ribonucleoproteins (NLM Chemicals)
KW  - tau Proteins (NLM Chemicals)
KW  - SRSF2 protein, human (NLM Chemicals)
KW  - Serine-Arginine Splicing Factors (NLM Chemicals)
KW  - annonacin (NLM Chemicals)
KW  - Electron Transport Complex I (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:25402454
C2  - pmc:PMC4234644
DO  - DOI:10.1371/journal.pone.0113070
UR  - https://pub.dzne.de/record/137639
ER  -