title: Tau interactome mapping based identification of Otub1 as Tau deubiquitinase involved in accumulation of pathological Tau forms in vitro and in vivo.
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.
authors.affiliation: Alzheimer Dementia Group, Institute of Neuroscience, Catholic University of Louvain, 1200, Brussels, Belgium.
authors.forename: Peng
authors.initials: P
authors.lastname: Wang
authors.affiliation: Cellzome GmbH, Molecular Discovery Research, GlaxoSmithKline, Meyerhofstrasse 1, Heidelberg, Germany.
authors.forename: Gerard
authors.initials: G
authors.lastname: Joberty
authors.affiliation: Department of Neuroscience, Janssen Research and Development, A Division of Janssen Pharmaceutica NV, 2340, Beerse, Belgium.
authors.forename: Arjan
authors.initials: A
authors.lastname: Buist
authors.affiliation: Alzheimer Dementia Group, Institute of Neuroscience, Catholic University of Louvain, 1200, Brussels, Belgium.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Vanoosthuyse
authors.affiliation: Alzheimer Dementia Group, Institute of Neuroscience, Catholic University of Louvain, 1200, Brussels, Belgium.
authors.forename: Ilie-Cosmin
authors.initials: IC
authors.lastname: Stancu
authors.affiliation: Alzheimer Dementia Group, Institute of Neuroscience, Catholic University of Louvain, 1200, Brussels, Belgium.
authors.forename: Bruno
authors.initials: B
authors.lastname: Vasconcelos
authors.affiliation: Alzheimer Dementia Group, Institute of Neuroscience, Catholic University of Louvain, 1200, Brussels, Belgium.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Pierrot
authors.affiliation: Cellzome GmbH, Molecular Discovery Research, GlaxoSmithKline, Meyerhofstrasse 1, Heidelberg, Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Faelth-Savitski
authors.affiliation: Alzheimer Dementia Group, Institute of Neuroscience, Catholic University of Louvain, 1200, Brussels, Belgium.
authors.forename: Pascal
authors.initials: P
authors.lastname: Kienlen-Campard
authors.affiliation: Alzheimer Dementia Group, Institute of Neuroscience, Catholic University of Louvain, 1200, Brussels, Belgium.
authors.forename: Jean-Noël
authors.initials: JN
authors.lastname: Octave
authors.affiliation: Cellzome GmbH, Molecular Discovery Research, GlaxoSmithKline, Meyerhofstrasse 1, Heidelberg, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Bantscheff
authors.affiliation: Cellzome GmbH, Molecular Discovery Research, GlaxoSmithKline, Meyerhofstrasse 1, Heidelberg, Germany.
authors.forename: Gerard
authors.initials: G
authors.lastname: Drewes
authors.affiliation: Department of Neuroscience, Janssen Research and Development, A Division of Janssen Pharmaceutica NV, 2340, Beerse, Belgium.
authors.forename: Diederik
authors.initials: D
authors.lastname: Moechars
authors.affiliation: Alzheimer Dementia Group, Institute of Neuroscience, Catholic University of Louvain, 1200, Brussels, Belgium. ilse.dewachter@uclouvain.be.|BioMedical Research Institute, Hasselt University, Hasselt, Belgium. ilse.dewachter@uclouvain.be.
authors.forename: Ilse
authors.initials: I
authors.lastname: Dewachter
mesh_terms: D000818:Animals; D003546:Cysteine Endopeptidases / Q000235:genetics*; D000072017:Deubiquitinating Enzymes / Q000378:metabolism*; D006801:Humans; D008822:Mice, Transgenic; D016874:Neurofibrillary Tangles / Q000378:metabolism / Q000473:pathology*; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D024801:Tauopathies / Q000378:metabolism / Q000473:pathology*; D025801:Ubiquitin / Q000378:metabolism; D054875:Ubiquitination / Q000502:physiology; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D025801:Ubiquitin; D016875:tau Proteins; D000072017:Deubiquitinating Enzymes; D003546:Cysteine Endopeptidases; C507756:Otub1 protein, mouse
keywords: Alzheimer’s disease; Interactome mapping; Otub1; Tau; Tau oligomerization; Tau pathology; Ubiquitination