TBK1 phosphorylates mutant Huntingtin and suppresses its aggregation and toxicity in Huntington's disease models.

Autor: Hegde RN; Laboratory of Molecular and Chemical Biology of Neurodegeneration, Brain Mind Institute, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland., Chiki A; Laboratory of Molecular and Chemical Biology of Neurodegeneration, Brain Mind Institute, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland., Petricca L; Department of Neuroscience, IRBM Science Park, Rome, Italy., Martufi P; Department of Neuroscience, IRBM Science Park, Rome, Italy., Arbez N; Division of Neurobiology, Department of Psychiatry and Departments of Neurology, Neuroscience and Pharmacology, Johns Hopkins University School of Medicine, Baltimore, MD, USA., Mouchiroud L; Laboratory of Integrative and Systems Physiology, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland., Auwerx J; Laboratory of Integrative and Systems Physiology, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland., Landles C; Huntington's Disease Centre, Department of Neurodegenerative Disease and UK Dementia Research Institute at UCL, Queen Square Institute of Neurology, University College London, London, UK., Bates GP; Huntington's Disease Centre, Department of Neurodegenerative Disease and UK Dementia Research Institute at UCL, Queen Square Institute of Neurology, University College London, London, UK., Singh-Bains MK; Centre for Brain Research, Department of Anatomy and Medical Imaging, University of Auckland, Auckland, New Zealand., Dragunow M; Centre for Brain Research, Department of Pharmacology and Clinical Pharmacology, University of Auckland, Auckland, New Zealand., Curtis MA; Centre for Brain Research, Department of Anatomy and Medical Imaging, University of Auckland, Auckland, New Zealand., Faull RL; Centre for Brain Research, Department of Anatomy and Medical Imaging, University of Auckland, Auckland, New Zealand., Ross CA; Division of Neurobiology, Department of Psychiatry and Departments of Neurology, Neuroscience and Pharmacology, Johns Hopkins University School of Medicine, Baltimore, MD, USA., Caricasole A; Department of Neuroscience, IRBM Science Park, Rome, Italy., Lashuel HA; Laboratory of Molecular and Chemical Biology of Neurodegeneration, Brain Mind Institute, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
Jazyk: angličtina
Zdroj: The EMBO journal [EMBO J] 2020 Sep 01; Vol. 39 (17), pp. e104671. Date of Electronic Publication: 2020 Aug 05.
DOI: 10.15252/embj.2020104671
Abstrakt: Phosphorylation of the N-terminal domain of the huntingtin (HTT) protein has emerged as an important regulator of its localization, structure, aggregation, clearance and toxicity. However, validation of the effect of bona fide phosphorylation in vivo and assessing the therapeutic potential of targeting phosphorylation for the treatment of Huntington's disease (HD) require the identification of the enzymes that regulate HTT phosphorylation. Herein, we report the discovery and validation of a kinase, TANK-binding kinase 1 (TBK1), that efficiently phosphorylates full-length and N-terminal HTT fragments in vitro (at S13/S16), in cells (at S13) and in vivo. TBK1 expression in HD models (cells, primary neurons, and Caenorhabditis elegans) increases mutant HTT exon 1 phosphorylation and reduces its aggregation and cytotoxicity. We demonstrate that the TBK1-mediated neuroprotective effects are due to phosphorylation-dependent inhibition of mutant HTT exon 1 aggregation and an increase in autophagic clearance of mutant HTT. These findings suggest that upregulation and/or activation of TBK1 represents a viable strategy for the treatment of HD by simultaneously lowering mutant HTT levels and blocking its aggregation.
(© 2020 The Authors. Published under the terms of the CC BY NC ND 4.0 license.)
Databáze: MEDLINE
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