1. TBK1 phosphorylates mutant Huntingtin and suppresses its aggregation and toxicity in Huntington's disease models.
- Author
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Hegde RN, Chiki A, Petricca L, Martufi P, Arbez N, Mouchiroud L, Auwerx J, Landles C, Bates GP, Singh-Bains MK, Dragunow M, Curtis MA, Faull RL, Ross CA, Caricasole A, and Lashuel HA
- Subjects
- Animals, Caenorhabditis elegans genetics, Caenorhabditis elegans Proteins genetics, Disease Models, Animal, HEK293 Cells, Humans, Huntingtin Protein genetics, Huntington Disease genetics, Phosphorylation, Protein Serine-Threonine Kinases genetics, Rats, Caenorhabditis elegans metabolism, Huntingtin Protein metabolism, Huntington Disease metabolism, Mutation, Protein Aggregates, Protein Serine-Threonine Kinases metabolism
- 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., (© 2020 The Authors. Published under the terms of the CC BY NC ND 4.0 license.)
- Published
- 2020
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