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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 | Source: | 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 | Keywords: | Alzheimer’s disease; interactome mapping; Otub1; Tau; Tau oligomerization; Tau pathology; ubiquitination | Document URI: | http://hdl.handle.net/1942/23691 | ISSN: | 0001-6322 | e-ISSN: | 1432-0533 | DOI: | 10.1007/s00401-016-1663-9 | ISI #: | 000399397300004 | Rights: | Copyright information: © The Author(s) 2017 Open Access: This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. | Category: | A1 | Type: | Journal Contribution | Validations: | ecoom 2018 |
Appears in Collections: | Research publications |
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Wang_Dewachter_Acta Neuropathologica.pdf | Published version | 3.14 MB | Adobe PDF | View/Open |
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