Premium
TBK1 phosphorylates mutant Huntingtin and suppresses its aggregation and toxicity in Huntington's disease models
Author(s) -
Hegde Ramanath Narayana,
Chiki Anass,
Petricca Lara,
Martufi Paola,
Arbez Nicolas,
Mouchiroud Laurent,
Auwerx Johan,
Landles Christian,
Bates Gillian P,
SinghBains Malvindar K,
Dragunow Mike,
Curtis Maurice A,
Faull Richard LM,
Ross Christopher A,
Caricasole Andrea,
Lashuel Hilal A
Publication year - 2020
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.2020104671
Subject(s) - huntingtin , biology , huntington's disease , phosphorylation , mutant , huntingtin protein , microbiology and biotechnology , toxicity , cancer research , genetics , disease , gene , medicine
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 ( TBK 1), that efficiently phosphorylates full‐length and N‐terminal HTT fragments in vitro (at S13/S16), in cells (at S13) and in vivo . TBK 1 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 TBK 1‐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 TBK 1 represents a viable strategy for the treatment of HD by simultaneously lowering mutant HTT levels and blocking its aggregation.