TBK1 interacts with tau and enhances neurodegeneration in tauopathy.
J Biol Chem
; 296: 100760, 2021.
Article
em En
| MEDLINE
| ID: mdl-33965374
ABSTRACT
One of the defining pathological features of Alzheimer's disease (AD) is the deposition of neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau in the brain. Aberrant activation of kinases in AD has been suggested to enhance phosphorylation and toxicity of tau, making the responsible tau kinases attractive therapeutic targets. The full complement of tau-interacting kinases in AD brain and their activity in disease remains incompletely defined. Here, immunoaffinity enrichment coupled with mass spectrometry (MS) identified TANK-binding kinase 1 (TBK1) as a tau-interacting partner in human AD cortical brain tissues. We validated this interaction in human AD, familial frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) caused by mutations in MAPT (R406W & P301L) and corticobasal degeneration (CBD) postmortem brain tissues as well as human cell lines. Further, we document increased TBK1 activation in both AD and FTDP-17 and map TBK1 phosphorylation sites on tau based on in vitro kinase assays coupled to MS. Lastly, in a Drosophila tauopathy model, activating expression of a conserved TBK1 ortholog triggers tau hyperphosphorylation and enhanced neurodegeneration, whereas knockdown had the reciprocal effect, suppressing tau toxicity. Collectively, our findings suggest that increased TBK1 activation may promote tau hyperphosphorylation and neuronal loss in AD and related tauopathies.
Palavras-chave
Alzheimer's disease (AD); Drosophila; IκB kinase (IKK); TANK-binding kinase 1 (TBK1); co-immunoprecipitation (co-IP); familial frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17); mass spectrometry (MS); microtubule-associated protein tau (MAPT); neurofibrillary tangles (NFTs); posttranslational modification (PTM)
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Proteínas tau
/
Proteínas Serina-Treonina Quinases
/
Tauopatias
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Doença de Alzheimer
/
Mapas de Interação de Proteínas
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Female
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Humans
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Male
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article