Mitochondrial Complex 1 Inhibition Increases 4-Repeat Isoform Tau by SRSF2 Upregulation
Open Access
- 17 November 2014
- journal article
- Published by Public Library of Science (PLoS) in PLOS ONE
- Vol. 9 (11), e113070
- https://doi.org/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.This publication has 28 references indexed in Scilit:
- Trans-splicing correction of tau isoform imbalance in a mouse model of tau mis-splicingHuman Molecular Genetics, 2013
- Rapid, complete and large‐scale generation of post‐mitotic neurons from the human LUHMES cell lineJournal of Neurochemistry, 2011
- MAPT Isoforms: Differential Transcriptional Profiles Related to 3R and 4R Splice VariantsJournal of Alzheimer's Disease, 2011
- Spliceosome Structure and FunctionCold Spring Harbor Perspectives in Biology, 2010
- Regulation of SR protein phosphorylation and alternative splicing by modulating kinetic interactions of SRPK1 with molecular chaperonesGenes & Development, 2009
- Atypical parkinsonism in Guadeloupe: a common risk factor for two closely related phenotypes?Brain, 2007
- Mitochondrial Complex I: structure, function, and implications in neurodegeneration.2007
- Tauopathies: classification and clinical update on neurodegenerative diseases associated with microtubule‐associated protein tauInternal Medicine Journal, 2006
- Mitochondrial Dysfunction in Cybrid Lines Expressing Mitochondrial Genes from Patients with Progressive Supranuclear PalsyJournal of Neurochemistry, 2000
- Mutation in the tau gene in familial multiple system tauopathy with presenile dementiaProceedings of the National Academy of Sciences of the United States of America, 1998