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

Autor: Paola Martufi, Richard L.M. Faull, Johan Auwerx, Malvindar K. Singh-Bains, Hilal A. Lashuel, Ramanath Narayana Hegde, Mike Dragunow, Andrea Caricasole, Christopher A. Ross, Anass Chiki, Christian Landles, Gillian P. Bates, Lara Petricca, Nicolas Arbez, Laurent Mouchiroud, Maurice A. Curtis
Rok vydání: 2020
Předmět:
autophagy
congenital
hereditary
and neonatal diseases and abnormalities
Huntingtin
TBK1
animal diseases
Mutant
Protein Serine-Threonine Kinases
Biology
Neuroprotection
Article
General Biochemistry
Genetics and Molecular Biology
Protein Aggregates
03 medical and health sciences
0302 clinical medicine
Huntington's disease
TANK-binding kinase 1
Downregulation and upregulation
mental disorders
medicine
Animals
Humans
Molecular Biology of Disease
Phosphorylation
Caenorhabditis elegans
Caenorhabditis elegans Proteins
Molecular Biology
030304 developmental biology
Huntingtin Protein
0303 health sciences
reducing aggregation
General Immunology and Microbiology
Kinase
General Neuroscience
Articles
medicine.disease
Rats
nervous system diseases
Cell biology
huntingtin phosphorylation
Disease Models
Animal
HEK293 Cells
Huntington Disease
nervous system
Mutation
030217 neurology & neurosurgery
Neuroscience
Zdroj: The EMBO Journal
ISSN: 1460-2075
0261-4189
DOI: 10.15252/embj.2020104671
Popis: 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.
Phosphorylation of the N‐terminal domain of Huntingtin (HTT) by TANK‐binding kinase 1 (TBK1) promotes its autophagic clearance and reduce its aggregation and cytotoxicity, suggesting new strategies for neuroprotective therapies.
Databáze: OpenAIRE
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