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

Ramanath Narayana Hegde, Anass Chiki, Lara Petricca, Paola Martufi, Nicolas Arbez, Laurent Mouchiroud, Johan Auwerx, Christian Landles, Gillian P. Bates, Malvindar K. Singh-Bains, Mike Dragunow, Maurice A. Curtis, Richard L.M. Faull, Christopher A. Ross, Andrea Caricasole, Hilal A. Lashuel

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article numbere104671
JournalEMBO Journal
Volume39
Issue number17
DOIs
StatePublished - Sep 1 2020

Keywords

  • Huntington's disease
  • TBK1
  • autophagy
  • huntingtin phosphorylation
  • reducing aggregation

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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  • Cite this

    Hegde, R. N., Chiki, A., Petricca, L., Martufi, P., Arbez, N., Mouchiroud, L., Auwerx, J., Landles, C., Bates, G. P., Singh-Bains, M. K., Dragunow, M., Curtis, M. A., Faull, R. L. M., Ross, C. A., Caricasole, A., & Lashuel, H. A. (2020). TBK1 phosphorylates mutant Huntingtin and suppresses its aggregation and toxicity in Huntington's disease models. EMBO Journal, 39(17), [e104671]. https://doi.org/10.15252/embj.2020104671