Annonacin, a natural lipophilic mitochondrial complex I inhibitor, increases phosphorylation of tau in the brain of EDP-17 transgenic mice
Annonacin, a natural lipophilic mitochondrial complex I inhibitor, increases phosphorylation of tau in the brain of EDP-17 transgenic mice
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DOI：
10.1016/j.expneurol.2013.12.017
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发表时间：
2014-03-01
影响因子：
5.3
通讯作者：
Hoeglinger, Guenter U.
中科院分区：
文献类型：
--
作者：
Yamada, Elizabeth S.;Respondek, Gesine;Hoeglinger, Guenter U.
遗传和环境因素都可能导致tau蛋白病的神经病理学，但目前尚不清楚特定的遗传背景如何影响对环境毒素的易感性。 tau 基因突变与家族性 tau 病有关，而安诺那酸（一种植物来源的线粒体抑制剂）与环境形式的 tau 病有关。因此，我们确定转基因小鼠中番荔枝酸暴露与 R406W-tau 突变表达之间是否存在致病协同作用。我们发现，与仅具有内源性小鼠 tau 的小鼠 (R406W(-/-)) 相比，暴露于番红花酸会导致 R406W(+/+) 小鼠几个大脑区域的体细胞树突区中具有磷酸化 tau 的神经元数量增加。蛋白质印迹分析表明，在安非那酸治疗后，R406W(+/+) 小鼠中总 tau 蛋白随之增加，而 tau mRNA 没有增加，但蛋白酶体蛋白水解活性降低，但 R406W(-/-) 小鼠则没有。磷酸化 tau 水平超过了总 tau 蛋白的增加，同时不同 tau 激酶水平也增加，最重要的是 p25/p35 比率显着增加，已知该比率可激活 tau 激酶 Cdk5。总之，我们观察到番荔枝酸暴露与 R406W-tau 突变存在之间的协同相互作用，导致神经元 tau 的降解减少、磷酸化增加和重新分布。 (C) 2014 Elsevier Inc. 保留所有权利。
Both genetic and environmental factors likely contribute to the neuropathology of tauopathies, but it remains unclear how specific genetic backgrounds affect the susceptibility towards environmental toxins. Mutations in the tau gene have been associated with familial tauopathies, while annonacin, a plant-derived mitochondrial inhibitor, has been implicated in an environmental form of tauopathy. We therefore determined whether there was a pathogenic synergy between annonacin exposure and the expression of the R406W-tau mutation in transgenic mice. We found that annonacin exposure caused an increase in the number of neurons with phosphorylated tau in the somatodendritic compartment in several brain areas in R406W(+/+) mice as opposed to mice that had only the endogenous mouse tau (R406W(-/-)). Western blot analysis demonstrated a concomitant increase in total tau protein without increase in tau mRNA, but reduced proteasomal proteolytic activity in R406W(+/+), but not R406W(-/-) mice, upon annonacin-treatment. Phosphorylated tau levels exceeded the increase in total tau protein, along with increased levels of different tau kinases, foremost a striking increase in the p25/p35 ratio, known to activate the tau kinase Cdk5. In summary, we observed a synergistic interaction between annonacin exposure and the presence of the R406W-tau mutation, which resulted in reduced degradation, increased phosphorylation and redistribution of neuronal tau. (C) 2014 Elsevier Inc. All rights reserved.