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Please use this identifier to cite or link to this item: http://hdl.handle.net/1942/23691

Title: Tau interactome mapping based identification of Otub1 as Tau deubiquitinase involved in accumulation of pathological Tau forms in vitro and in vivo
Authors: Wang, Peng
Joberty, Gerard
Buist, Arjan
Vanoosthuyse, Alexandre
Stancu, Ilie-Cosmin
Vasconcelos, Bruno
Pierrot, Nathalie
Faelth-Savitski, Maria
Kienlen-Campard, Pascal
Octave, Jean-Noël
Bantscheff, Marcus
Drewes, Gerard
Moechars, Diederik
Dewachter, Ilse
Issue Date: 2017
Citation: ACTA NEUROPATHOLOGICA, 133(5), p. 731-749
Abstract: Dysregulated proteostasis is a key feature of a variety of neurodegenerative disorders. In Alzheimer's disease (AD), progression of symptoms closely correlates with spatiotemporal progression of Tau aggregation, with "early" oligomeric Tau forms rather than mature neurofibrillary tangles (NFTs) considered to be pathogenetic culprits. The ubiquitin-proteasome system (UPS) controls degradation of soluble normal and abnormally folded cytosolic proteins. The UPS is affected in AD and is identified by genomewide association study (GWAS) as a risk pathway for AD. The UPS is determined by balanced regulation of ubiquitination and deubiquitination. In this work, we performed isobaric tags for relative and absolute quantitation (iTRAQ)-based Tau interactome mapping to gain unbiased insight into Tau pathophysiology and to identify novel Tau-directed therapeutic targets. Focusing on Tau deubiquitination, we here identify Otub1 as a Tau-deubiquitinating enzyme. Otub1 directly affected Lys48-linked Tau deubiquitination, impairing Tau degradation, dependent on its catalytically active cysteine, but independent of its noncanonical pathway modulated by its N-terminal domain in primary neurons. Otub1 strongly increased AT8-positive Tau and oligomeric Tau forms and increased Tau-seeded Tau aggregation in primary neurons. Finally, we demonstrated that expression of Otub1 but not its catalytically inactive form induced pathological Tau forms after 2 months in Tau transgenic mice in vivo, including AT8-positive Tau and oligomeric Tau forms. Taken together, we here identified Otub1 as a Tau deubiquitinase in vitro and in vivo, involved in formation of pathological Tau forms, including small soluble oligomeric forms. Otub1 and particularly Otub1 inhibitors, currently under development for cancer therapies, may therefore yield interesting novel therapeutic avenues for Tauopathies and AD.
Notes: Dewachter, I (reprint author), Catholic Univ Louvain, Inst Neurosci, Alzheimer Dementia Grp, B-1200 Brussels, Belgium.ilse.dewachter@uclouvain.be
URI: http://hdl.handle.net/1942/23691
DOI: 10.1007/s00401-016-1663-9
ISI #: 000399397300004
ISSN: 0001-6322
Category: A1
Type: Journal Contribution
Appears in Collections: Research publications

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