Lookup NU author(s): Professor Tiago Outeiro
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© The Author 2014. Published by Oxford University Press. All rights reserved.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.
Author(s): Blum D, Herrera F, Francelle L, Mendes T, Basquin M, Obriot H, Demeyer D, Sergeant N, Gerhardt E, Brouillet E, Buée L, Outeiro TF
Publication type: Article
Publication status: Published
Journal: Human Molecular Genetics
Print publication date: 01/01/2015
Online publication date: 20/08/2014
Acceptance date: 14/08/2014
ISSN (print): 0964-6906
ISSN (electronic): 1460-2083
Publisher: Oxford University Press
PubMed id: 25143394
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