TBK1 phosphorylates mutant Huntingtin and suppresses its aggregation and toxicity in Huntington's disease models
Open Access
- 5 August 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in The EMBO Journal
- Vol. 39 (17), e104671
- https://doi.org/10.15252/embj.2020104671
Abstract
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.Keywords
Funding Information
- CHDI Foundation
- École Polytechnique Fédérale de Lausanne
- National Institute of Neurological Disorders and Stroke (R01 NS086452, R21 NS083365)
This publication has 98 references indexed in Scilit:
- Polo-like kinase 2 regulates selective autophagic α-synuclein clearance and suppresses its toxicity in vivoProceedings of the National Academy of Sciences of the United States of America, 2013
- Polyglutamine domain flexibility mediates the proximity between flanking sequences in huntingtinProceedings of the National Academy of Sciences of the United States of America, 2013
- Huntington's Disease and the Striatal Medium Spiny Neuron: Cell-Autonomous and Non-Cell-Autonomous Mechanisms of DiseaseNeurotherapeutics, 2012
- Ganglioside GM1 induces phosphorylation of mutant huntingtin and restores normal motor behavior in Huntington disease miceProceedings of the National Academy of Sciences of the United States of America, 2012
- Affinity Purification of Protein Complexes in C. elegansMethods in Cell Biology, 2011
- Serines 13 and 16 Are Critical Determinants of Full-Length Human Mutant Huntingtin Induced Disease Pathogenesis in HD MiceNeuron, 2009
- Phosphorylation of Threonine 3Online Journal of Public Health Informatics, 2009
- Phosphorylation at Ser-129 but Not the Phosphomimics S129E/D Inhibits the Fibrillation of α-SynucleinJournal of Biological Chemistry, 2008
- Inclusion body formation reduces levels of mutant huntingtin and the risk of neuronal deathNature, 2004
- Self-assembly of polyglutamine-containing huntingtin fragments into amyloid-like fibrils: Implications for Huntington’s disease pathologyProceedings of the National Academy of Sciences of the United States of America, 1999