Department of Biochemistry, Emory University School of Medicine, Atlanta, Georgia, USA; Center for Neurodegenerative Diseases, Emory University School of Medicine, Atlanta, Georgia, USA.
Department of Neurology, Baylor College of Medicine, Houston, Texas, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas, USA.
J Biol Chem. 2021 Jan-Jun;296:100760. doi: 10.1016/j.jbc.2021.100760. Epub 2021 May 7.
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.
阿尔茨海默病 (AD) 的一个定义性病理学特征是大脑中神经原纤维缠结 (NFT) 的沉积，NFT 由过度磷酸化的 tau 组成。AD 中激酶的异常激活被认为增强了 tau 的磷酸化和毒性，使负责的 tau 激酶成为有吸引力的治疗靶点。AD 大脑中 tau 相互作用激酶的全部成分及其在疾病中的活性仍不完全确定。在这里，免疫亲和富集与质谱 (MS) 相结合，鉴定出 TANK 结合激酶 1 (TBK1) 是人类 AD 皮质脑组织中与 tau 相互作用的伴侣。我们在人类 AD、家族性额颞叶痴呆和与染色体 17 相关的帕金森病 (FTDP-17)（由 MAPT 中的突变引起，R406W 和 P301L）和皮质基底节变性 (CBD) 尸检脑组织以及人类细胞系中验证了这种相互作用。此外，我们记录了 AD 和 FTDP-17 中 TBK1 激活的增加，并根据体外激酶测定和 MS 绘制了基于 tau 的 TBK1 磷酸化位点。最后，在果蝇 tau 病模型中，激活保守的 TBK1 同源物的表达会引发 tau 过度磷酸化和增强的神经退行性变，而敲低则具有相反的效果，抑制 tau 毒性。总的来说，我们的研究结果表明，TBK1 激活的增加可能会促进 AD 和相关 tau 病中 tau 的过度磷酸化和神经元丢失。
