RT Journal Article SR Electronic T1 TBK1 interacts with tau and enhances neurodegeneration in tauopathy JF bioRxiv FD Cold Spring Harbor Laboratory SP 2020.06.17.157552 DO 10.1101/2020.06.17.157552 A1 Measho H. Abreha A1 Shamsideen Ojelade A1 Eric B. Dammer A1 Zachary T. McEachin A1 Duc M. Duong A1 Marla Gearing A1 Gary J. Bassell A1 James J. Lah A1 Allan I. Levey A1 Joshua M. Shulman A1 Nicholas T. Seyfried YR 2020 UL http://biorxiv.org/content/early/2020/06/18/2020.06.17.157552.abstract AB 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-directed 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 both human AD and familial frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) caused by mutations in MAPT (R406W) postmortem brain tissues as well as human cell lines. Further, we document increased TBK1 activity in both AD and FTDP-17 and map the predominant 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 activity may promote tau hyperphosphorylation and neuronal loss in AD and related tauopathies.Competing Interest StatementThe authors have declared no competing interest.