Glycolytic preconditioning in astrocytes mitigates trauma-induced neurodegeneration.
Glycolytic preconditioning in astrocytes mitigates trauma-induced neurodegeneration.
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DOI：
10.7554/elife.69438
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发表时间：
2021-09-02
期刊：
影响因子：
7.7
通讯作者：
Douglas PM
中科院分区：
文献类型：
--
作者：
Solano Fonseca R;Metang P;Egge N;Liu Y;Zuurbier KR;Sivaprakasam K;Shirazi S;Chuah A;Arneaud SL;Konopka G;Qian D;Douglas PM
脑震荡与许多有害的直接和长期后果有关。然而，促进不同神经亚型对功能障碍和退化的选择性脆弱性的分子机制和遗传靶点仍不清楚。将秀丽隐杆线虫钝力创伤实验模型转化为小鼠脑震荡，我们发现了一种保守的神经保护机制，其中通过复合物 IV 减少线粒体电子通量，抑制了创伤引起的高度脆弱的多巴胺能神经元的退化。降低细胞色素 C 氧化酶功能会提高线粒体衍生的活性氧，该活性氧通过细胞质缺氧诱导转录因子 Hif1a 发出信号，促进丙酮酸脱氢酶 PDHE1α 的过度磷酸化和失活。这种关键酶启动 Warburg 分流，以神经保护的方式驱动能量从线粒体呼吸重新分配到星形胶质细胞介导的糖酵解。这些研究证明了一个保守的过程，其中糖酵解预处理通过氧化还原信号和瓦尔堡效应抑制多巴胺能神经元对创伤引起的变性的帕金森样超敏反应。脑震荡是一种创伤性脑损伤，由头部突然受到打击或摇晃引起。症状可能包括短暂的头痛、头晕、意识混乱或对光敏感，但经历多次脑震荡可能会对以后的生活产生巨大的影响。对职业运动员的研究表明，经历过一次或多次脑震荡的人容易患上阿尔茨海默氏症和帕金森氏症，这两种众所周知的神经退行性疾病。这两种情况都涉及神经细胞（称为神经元）的逐渐丧失或破坏。但这种所谓的脑细胞神经变性到底是如何源于最初的身体损伤仍不清楚。头部创伤可能会导致细胞的结构支撑受损或破坏神经元的电脉冲流动。受损细胞的能量使用和生产可能会过度驱动以修复损伤。不同类型脑细胞的化学特性也可能使某些脑细胞比其他脑细胞更容易受到创伤。除了神经元之外，大脑中称为星形胶质细胞的星形支持细胞可能具有一定的保护能力，也可能受到影响。为了研究哪些细胞可能更容易受到外伤，Solano Fonseca 等人。模拟了蛔虫（线虫）和小鼠脑震荡样头部创伤的影响。在这两种动物中，一种类型的神经元在创伤后极易发生细胞死亡。释放多巴胺（一种参与细胞间通讯和大脑奖励系统的化学物质）的神经元显示出细胞损伤的迹象，并在受伤后恶化。多巴胺能细胞（这些细胞被称为多巴胺能细胞）参与运动协调，多巴胺能细胞的丧失与阿尔茨海默病和帕金森病有关。然而，星形胶质细胞在减少创伤后多巴胺能神经元的死亡方面发挥着作用。在实验中，星形胶质细胞似乎恢复了能量产生的平衡，以满足受影响神经元增加的能量需求。单细胞分析表明，星形胶质细胞中参与新陈代谢的基因被打开，通过替代途径产生能量。通过星形胶质细胞促进的这种能量转变可能有助于减轻创伤后对产生多巴胺的神经元的一些损害，从而减少细胞死亡。这项工作进一步加深了我们对脑震荡大脑细胞变化的理解。需要更多的研究来更好地描述这种对细胞的直接创伤以及随后的多巴胺能神经元的丧失如何影响大脑的长期健康。随后可能会努力设计有效的疗法来减缓或逆转这些变化。
Concussion is associated with a myriad of deleterious immediate and long-term consequences. Yet the molecular mechanisms and genetic targets promoting the selective vulnerability of different neural subtypes to dysfunction and degeneration remain unclear. Translating experimental models of blunt force trauma in C. elegans to concussion in mice, we identify a conserved neuroprotective mechanism in which reduction of mitochondrial electron flux through complex IV suppresses trauma-induced degeneration of the highly vulnerable dopaminergic neurons. Reducing cytochrome C oxidase function elevates mitochondrial-derived reactive oxygen species, which signal through the cytosolic hypoxia inducing transcription factor, Hif1a, to promote hyperphosphorylation and inactivation of the pyruvate dehydrogenase, PDHE1α. This critical enzyme initiates the Warburg shunt, which drives energetic reallocation from mitochondrial respiration to astrocyte-mediated glycolysis in a neuroprotective manner. These studies demonstrate a conserved process in which glycolytic preconditioning suppresses Parkinson-like hypersensitivity of dopaminergic neurons to trauma-induced degeneration via redox signaling and the Warburg effect. Concussion is a type of traumatic brain injury that results from a sudden blow or jolt to the head. Symptoms can include a passing headache, dizziness, confusion or sensitivity to light, but experiencing multiple concussions can have drastic repercussions in later life. Studies of professional athletes have shown that those who experience one or more concussions are prone to developing Alzheimer’s and Parkinson’s disease, two well-known neurodegenerative diseases. Both conditions involve the progressive loss or breakdown of nerve cells, called neurons. But exactly how this so-called neurodegeneration of brain cells stems from the original, physical injury remains unclear. Head trauma may cause damage to the structural support of a cell or disrupt the flow of electrical impulses through neurons. Energy use and production in damaged cells could shift into overdrive to repair the damage. The chemical properties of different types of brain cells could also make some more vulnerable to trauma than others. Besides neurons, star-shaped support cells in the brain called astrocytes, which may have some protective ability, could also be affected. To investigate which cells may be more susceptible to traumatic injuries, Solano Fonseca et al. modelled the impacts of concussion-like head trauma in roundworms (C. elegans) and mice. In both animals, one type of neuron was extremely vulnerable to cell death after trauma. Neurons that release dopamine, a chemical involved in cell-to-cell communication and the brain’s reward system, showed signs of cell damage and deteriorated after injury. Dopaminergic cells, as these cells are called, are involved in motor coordination, and the loss of dopaminergic cells has been linked to both Alzheimer’s and Parkinson’s disease. Astrocytes, however, had a role in reducing the death of dopaminergic neurons after trauma. In experiments, astrocytes appeared to restore the balance of energy production to meet the increased energy demands of impacted neurons. Single-cell analyses showed that genes involved in metabolism were switched on in astrocytes to produce energy via an alternative pathway. This energetic shift facilitated via astrocytes may help mitigate against some damage to dopamine-producing neurons after trauma, reducing cell death. This work furthers our understanding of cellular changes in the concussed brain. More research will be required to better characterise how this immediate trauma to cells, and the subsequent loss of dopaminergic neurons, impacts brain health long-term. Efforts to design effective therapies to slow or reverse these changes could then follow.