GSK3β-mediated tau hyperphosphorylation triggers diabetic retinal neurodegeneration by disrupting synaptic and mitochondrial functions.
GSK3β-mediated tau hyperphosphorylation triggers diabetic retinal neurodegeneration by disrupting synaptic and mitochondrial functions.
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GSK3β 介导的 tau 蛋白过度磷酸化通过破坏突触和线粒体功能引发糖尿病视网膜神经变性
DOI：
10.1186/s13024-018-0295-z
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发表时间：
2018-11-22
影响因子：
15.1
通讯作者：
Ying Y
中科院分区：
文献类型：
--
作者：
Zhu H;Zhang W;Zhao Y;Shu X;Wang W;Wang D;Yang Y;He Z;Wang X;Ying Y
尽管糖尿病视网膜病变（DR）长期以来被认为是微血管疾病，但越来越多的证据表明糖尿病视网膜神经变性，特别是视网膜神经节细胞（RGC）的突触丢失和功能障碍可能先于视网膜微血管变化。参与这一过程的关键分子仍不明确。微管相关蛋白tau是阿尔茨海默病（AD）和其他神经退行性疾病中神经毒性的关键介质。然而，tau蛋白在糖尿病诱导的视网膜神经变性中的作用（如果有的话）尚未确定。在这里，我们调查的变化和假定的作用，内源性tau蛋白在糖尿病视网膜神经变性。为此，我们结合联合收割机临床上使用的电生理技术，即图形视网膜电图和视觉诱发电位，并在一个良好的特点高脂饮食（HFD）诱导的小鼠糖尿病模型在体内和原代视网膜神经节细胞（RGC）在体外的分子分析。我们首次证明了通过GSK 3 β激活的tau蛋白过度磷酸化导致HFD诱导的DR中RGCs的视觉缺陷和突触丢失，这先于视网膜微血管病变和RGCs凋亡。此外，委员会认为，玻璃体内施用靶向tau的siRNA或GSK 3 β的特异性抑制剂通过在DR的一定时间范围内减弱tau过度磷酸化来逆转突触损失并恢复RGC的视觉功能。过度磷酸化的tau在糖脂毒性时诱导RGC的突触损失的细胞机制包括i）使微管轨道不稳定并损害微管-神经元的连接。依赖性突触靶向货物如mRNA和线粒体; ii）以GSK 3 β依赖性方式破坏通过线粒体的突触能量产生。我们的研究提出轻度视网膜tau蛋白病变作为DR的新病理生理学模型，tau蛋白作为新的治疗靶点，以对抗视网膜血管系统异常之前发生的糖尿病RGCs神经变性。本文的在线版本（10.1186/s13024-018-0295-z）包含补充材料，可供授权用户使用。
Although diabetic retinopathy (DR) has long been considered as a microvascular disorder, mounting evidence suggests that diabetic retinal neurodegeneration, in particular synaptic loss and dysfunction of retinal ganglion cells (RGCs) may precede retinal microvascular changes. Key molecules involved in this process remain poorly defined. The microtubule-associated protein tau is a critical mediator of neurotoxicity in Alzheimer’s disease (AD) and other neurodegenerative diseases. However, the effect of tau, if any, in the context of diabetes-induced retinal neurodegeneration has yet to be ascertained. Here, we investigate the changes and putative roles of endogeneous tau in diabetic retinal neurodegeneration. To this aim, we combine clinically used electrophysiological techniques, i.e. pattern electroretinogram and visual evoked potential, and molecular analyses in a well characterized high-fat diet (HFD)-induced mouse diabetes model in vivo and primary retinal ganglion cells (RGCs) in vitro. We demonstrate for the first time that tau hyperphosphorylation via GSK3β activation causes vision deficits and synapse loss of RGCs in HFD-induced DR, which precedes retinal microvasculopathy and RGCs apoptosis. Moreover, intravitreal administration of an siRNA targeting to tau or a specific inhibitor of GSK3β reverses synapse loss and restores visual function of RGCs by attenuating tau hyperphosphorylation within a certain time frame of DR. The cellular mechanisms by which hyperphosphorylated tau induces synapse loss of RGCs upon glucolipotoxicity include i) destabilizing microtubule tracks and impairing microtubule-dependent synaptic targeting of cargoes such as mRNA and mitochondria; ii) disrupting synaptic energy production through mitochondria in a GSK3β-dependent manner. Our study proposes mild retinal tauopathy as a new pathophysiological model for DR and tau as a novel therapeutic target to counter diabetic RGCs neurodegeneration occurring before retinal vasculature abnormalities. The online version of this article (10.1186/s13024-018-0295-z) contains supplementary material, which is available to authorized users.
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影响因子：
15.1
作者：
Lasagna-Reeves CA;Castillo-Carranza DL;Sengupta U;Clos AL;Jackson GR;Kayed R
通讯作者：
Kayed R
影响因子：
15.9
作者：
Barber, AJ;Lieth, E;Gardner, TW
通讯作者：
Gardner, TW
影响因子：
4.4
作者：
Chang, Richard Cheng-An;Shi, Liheng;Ko, Gladys Y. -P.
通讯作者：
Ko, Gladys Y. -P.
影响因子：
3.4
作者：
Eyman, Maria;Cefaliello, Carolina;Giuditta, Antonio
通讯作者：
Giuditta, Antonio
影响因子：
4.8
作者：
Liberman, Z;Eldar-Finkelman, H
通讯作者：
Eldar-Finkelman, H