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@ARTICLE{Bruch:137639,
author = {Bruch, Julius and Xu, Hong and De Andrade, Anderson and
Höglinger, Günter},
title = {{M}itochondrial complex 1 inhibition increases 4-repeat
isoform tau by {SRSF}2 upregulation.},
journal = {PLOS ONE},
volume = {9},
number = {11},
issn = {1932-6203},
address = {San Francisco, California, US},
publisher = {PLOS},
reportid = {DZNE-2020-03961},
pages = {e113070},
year = {2014},
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.},
keywords = {Alternative Splicing / Electron Transport Complex I:
antagonists $\&$ inhibitors / Electron Transport Complex I:
metabolism / Female / Furans: pharmacology / Gene Expression
Regulation: drug effects / Humans / Lactones: pharmacology /
Nuclear Proteins: metabolism / Oxidative Stress / Protein
Interaction Domains and Motifs / RNA Isoforms /
Ribonucleoproteins: metabolism / Serine-Arginine Splicing
Factors / Supranuclear Palsy, Progressive: genetics /
Supranuclear Palsy, Progressive: metabolism / Up-Regulation
/ tau Proteins: chemistry / tau Proteins: genetics / tau
Proteins: metabolism / Furans (NLM Chemicals) / Lactones
(NLM Chemicals) / Nuclear Proteins (NLM Chemicals) / RNA
Isoforms (NLM Chemicals) / Ribonucleoproteins (NLM
Chemicals) / tau Proteins (NLM Chemicals) / SRSF2 protein,
human (NLM Chemicals) / Serine-Arginine Splicing Factors
(NLM Chemicals) / annonacin (NLM Chemicals) / Electron
Transport Complex I (NLM Chemicals)},
cin = {AG Höglinger 1},
ddc = {610},
cid = {I:(DE-2719)1110002},
pnm = {344 - Clinical and Health Care Research (POF3-344)},
pid = {G:(DE-HGF)POF3-344},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:25402454},
pmc = {pmc:PMC4234644},
doi = {10.1371/journal.pone.0113070},
url = {https://pub.dzne.de/record/137639},
}