TBK1 interacts with tau and enhances neurodegeneration in tauopathy.
TBK1 interacts with tau and enhances neurodegeneration in tauopathy.
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DOI：
10.1016/j.jbc.2021.100760
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发表时间：
2021-01
期刊：
影响因子：
--
通讯作者：
Seyfried NT
中科院分区：
文献类型：
--
作者：
Abreha MH;Ojelade S;Dammer EB;McEachin ZT;Duong DM;Gearing M;Bassell GJ;Lah JJ;Levey AI;Shulman JM;Seyfried NT
阿尔茨海默病（AD）的定义性病理特征之一是脑中由过度磷酸化的tau组成的神经元缠结（NFT）的沉积。AD中激酶的异常激活已被认为增强tau的磷酸化和毒性，使得负责的tau激酶成为有吸引力的治疗靶标。AD脑中tau相互作用激酶的完整补体及其在疾病中的活性仍然不完全确定。在这里，免疫亲和富集结合质谱（MS）鉴定TANK结合激酶1（TBK 1）作为人类AD皮质脑组织中的tau相互作用伴侣。我们在人类AD、家族性额颞叶痴呆和与17号染色体（FTDP-17）相关的帕金森综合征（由MAPT（R406 W和P301 L）突变引起）和皮质基底节变性（CBD）死后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TBK 1激活的增加，并基于与MS偶联的体外激酶测定，绘制了tau蛋白上的TBK 1磷酸化位点。最后，在果蝇tau蛋白病模型中，激活保守的TBK 1直系同源物的表达触发tau蛋白过度磷酸化和增强神经变性，而敲低具有相互作用，抑制tau蛋白毒性。总的来说，我们的研究结果表明，增加TBK 1激活可能会促进AD和相关tau蛋白病中tau蛋白过度磷酸化和神经元丢失。
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.
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影响因子：
29
作者：
Freischmidt, Axel;Mueller, Kathrin;Andersen, Peter M.
通讯作者：
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影响因子：
4.2
作者：
Borghero G;Pugliatti M;Marrosu F;Marrosu MG;Murru MR;Floris G;Cannas A;Occhineri P;Cau TB;Loi D;Ticca A;Traccis S;Manera U;Canosa A;Moglia C;Calvo A;Barberis M;Brunetti M;Gibbs JR;Renton AE;Errichiello E;Zoledziewska M;Mulas A;Qian Y;Din J;Pliner HA;Traynor BJ;Chiò A;ITALSGEN and SARDINALS Consortia
通讯作者：
ITALSGEN and SARDINALS Consortia
影响因子：
82.9
作者：
Alonso, AD;GrundkeIqbal, I;Iqbal, K
通讯作者：
Iqbal, K
DOI：
10.1073/pnas.121119298
发表时间：
2001-06-05
影响因子：
11.1
作者：
Alonso, AD;Zaidi, T;Iqbal, K
通讯作者：
Iqbal, K
影响因子：
4.8
作者：
Clark, Kristopher;Plater, Lorna;Cohen, Philip
通讯作者：
Cohen, Philip