Mitochondrial ROS control neuronal excitability and cell fate in frontotemporal dementia
Mitochondrial ROS control neuronal excitability and cell fate in frontotemporal dementia
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线粒体ROS控制额颞叶痴呆的神经元兴奋性和细胞命运
DOI：
10.1002/alz.12394
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发表时间：
2021-05-31
影响因子：
14
通讯作者：
Abramov, Andrey Y.
中科院分区：
文献类型：
--
作者：
Esteras, Noemi;Kopach, Olga;Abramov, Andrey Y.
前言第二种最常见的早发性痴呆--额颞叶痴呆(FTD)--通常以微管相关蛋白tau聚集为特征。本研究通过FTD相关的10+16 MAPT突变，研究了tau诱导神经元功能障碍的机制。方法采用活体成像、电生理学和氧化还原蛋白质组学的方法，对10+16诱导的多能干细胞来源的神经元和原代培养的tau扩散模型进行研究。结果10+16神经元中线粒体活性氧(ROS)的过量产生通过氧化还原调节改变特异性谷氨酸受体亚单位的转运。Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic酸和N-甲基-D-天冬氨酸受体的表面表达增加，导致谷氨酸能信号转导受损、钙超载和兴奋性毒性。线粒体抗氧化剂恢复改变的反应，防止神经元死亡。重要的是，细胞外4R tau在正常神经元中诱导了相同的病理反应，从而提出了一种疾病传播的机制。
Introduction The second most common form of early-onset dementia-frontotemporal dementia (FTD)-is often characterized by the aggregation of the microtubule-associated protein tau. Here we studied the mechanism of tau-induced neuronal dysfunction in neurons with the FTD-related 10+16 MAPT mutation.Methods Live imaging, electrophysiology, and redox proteomics were used in 10+16 induced pluripotent stem cell-derived neurons and a model of tau spreading in primary cultures.Results Overproduction of mitochondrial reactive oxygen species (ROS) in 10+16 neurons alters the trafficking of specific glutamate receptor subunits via redox regulation. Increased surface expression of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptors containing GluA1 and NR2B subunits leads to impaired glutamatergic signaling, calcium overload, and excitotoxicity. Mitochondrial antioxidants restore the altered response and prevent neuronal death. Importantly, extracellular 4R tau induces the same pathological response in healthy neurons, thus proposing a mechanism for disease propagation.Discussion These results demonstrate mitochondrial ROS modulate glutamatergic signaling in FTD, and suggest a new therapeutic strategy.