title: Mutant huntingtin alters Tau phosphorylation and subcellular distribution.
abstract: Tau abnormalities play a central role in several neurodegenerative diseases, collectively known as tauopathies. In the present study, we examined whether mutant huntingtin (mHtt), which causes Huntington's disease (HD), modifies Tau phosphorylation and subcellular localization using cell and mouse HD models. Initially, we used novel bimolecular fluorescence complementation assays in live cells to evaluate Tau interactions with either wild type (25QHtt) or mutant huntingtin (103QHtt). While 25QHtt and Tau interacted at the level of the microtubule network, 103QHtt and Tau interacted and formed 'ring-like' inclusions localized in the vicinity of the microtubular organizing center (MTOC). Fluorescence recovery after photobleaching experiments also indicated that, whereas homomeric 103QHtt/103QHtt pairs rapidly re-entered into inclusions, heteromeric 103QHtt/Tau pairs remained excluded from the 'ring-like' inclusions. Interestingly, in vitro Tau relocalization was associated to Tau hyperphosphorylation. Consistent with this observation, we found strong Tau hyperphosphorylation in brain samples from two different mouse models of HD, R6/2 and 140CAG knock-in. This was associated with a significant reduction in the levels of Tau phosphatases (PP1, PP2A and PP2B), with no apparent involvement of major Tau kinases. Thus, the present study strongly suggests that expression of mHtt leads to Tau hyperphosphorylation, relocalization and sequestration through direct protein-protein interactions in inclusion-like compartments in the vicinity of the MTOC. Likewise, our data also suggest that Tau alterations may also contribute to HD pathogenesis.
authors.affiliation: Université Lille-Nord de France, UDSL, F-59000, Lille, France Inserm U837, Jean-Pierre Aubert Research Centre, IMPRT, F-59000, Lille, France CHRU, F-59000, Lille, France david.blum@inserm.fr touteiro@gmail.com.
authors.forename: David
authors.initials: D
authors.lastname: Blum
authors.affiliation: Cell and Molecular Neuroscience Unit, Instituto de Medicina Molecular, Av. Prof. Egas Moniz, 1649-029 Lisboa, Portugal.
authors.forename: Federico
authors.initials: F
authors.lastname: Herrera
authors.affiliation: CEA, DSV, I²BM, Molecular Imaging Research Center (MIRCen), Fontenay-aux-Roses F-92265, France and CNRS, CEA URA 2210, Fontenay-aux-Roses F-92265, France.
authors.forename: Laetitia
authors.initials: L
authors.lastname: Francelle
authors.affiliation: Cell and Molecular Neuroscience Unit, Instituto de Medicina Molecular, Av. Prof. Egas Moniz, 1649-029 Lisboa, Portugal david.blum@inserm.fr touteiro@gmail.com.
authors.forename: Tiago
authors.initials: T
authors.lastname: Mendes
authors.affiliation: Université Lille-Nord de France, UDSL, F-59000, Lille, France Inserm U837, Jean-Pierre Aubert Research Centre, IMPRT, F-59000, Lille, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Basquin
authors.affiliation: Université Lille-Nord de France, UDSL, F-59000, Lille, France Inserm U837, Jean-Pierre Aubert Research Centre, IMPRT, F-59000, Lille, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Obriot
authors.affiliation: Université Lille-Nord de France, UDSL, F-59000, Lille, France Inserm U837, Jean-Pierre Aubert Research Centre, IMPRT, F-59000, Lille, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Demeyer
authors.affiliation: Université Lille-Nord de France, UDSL, F-59000, Lille, France Inserm U837, Jean-Pierre Aubert Research Centre, IMPRT, F-59000, Lille, France CHRU, F-59000, Lille, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Sergeant
authors.affiliation: Department of Neurodegeneration and Restorative Research, Center for Nanoscale Microscopy and Molecular Physiology of the Brain, University Medical Center Goettingen, Waldweg 33, 37073 Goettingen, Germany.
authors.forename: Ellen
authors.initials: E
authors.lastname: Gerhardt
authors.affiliation: CEA, DSV, I²BM, Molecular Imaging Research Center (MIRCen), Fontenay-aux-Roses F-92265, France and CNRS, CEA URA 2210, Fontenay-aux-Roses F-92265, France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Brouillet
authors.affiliation: Université Lille-Nord de France, UDSL, F-59000, Lille, France Inserm U837, Jean-Pierre Aubert Research Centre, IMPRT, F-59000, Lille, France CHRU, F-59000, Lille, France.
authors.forename: Luc
authors.initials: L
authors.lastname: Buée
authors.affiliation: Cell and Molecular Neuroscience Unit, Instituto de Medicina Molecular, Av. Prof. Egas Moniz, 1649-029 Lisboa, Portugal Department of Neurodegeneration and Restorative Research, Center for Nanoscale Microscopy and Molecular Physiology of the Brain, University Medical Center Goettingen, Waldweg 33, 37073 Goettingen, Germany.
authors.forename: Tiago F
authors.initials: TF
authors.lastname: Outeiro
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D002478:Cells, Cultured; D004195:Disease Models, Animal; D057809:HEK293 Cells; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D022101:Microtubule-Organizing Center / Q000378:metabolism; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation; D021381:Protein Transport; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics* / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism*
chemical_list: C086055:HTT protein, human; D000071058:Huntingtin Protein; C054369:MAPT protein, human; C558298:Mapt protein, mouse; D009419:Nerve Tissue Proteins; D050486:Serotonin Plasma Membrane Transport Proteins; C493231:Slc6a4 protein, mouse; D016875:tau Proteins