Complexity of Astrocyte-Motor Neuron Interactions in Amyotrophic Lateral Sclerosis
Complexity of Astrocyte-Motor Neuron Interactions in Amyotrophic Lateral Sclerosis
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DOI：
10.1159/000089619
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发表时间：
2005-01-01
影响因子：
3
通讯作者：
Barbeito, Luis
中科院分区：
文献类型：
--
作者：
Pehar, Mariana;Vargas, Marcelo R.;Barbeito, Luis
神经元和周围的神经胶质细胞组成了一个高度专业化的功能单位。在肌萎缩侧索硬化症(ALS)中，星形胶质细胞与运动神经元以一种复杂的方式相互作用，调节神经元的存活。用表达ALS连锁突变的嵌合小鼠进行的实验表明，邻近的非神经细胞类型对疾病表型产生了关键的调制作用。当受到原发神经元损伤的干扰时，例如表达SOD-1突变，神经元可以向星形胶质细胞发出信号，使其增殖并变得活跃。成纤维细胞生长因子-1(成纤维细胞生长因子-1)可由运动神经元对损伤作出反应，通过FGFR1受体信号通路诱导星形胶质细胞激活。成纤维细胞生长因子-1刺激神经生长因子(NGF)的表达和分泌，以及核因子红系相关因子2(NRF2)转录因子的活性。NRF2导致抗氧化剂和细胞保护酶的表达，如血红素加氧酶-1和一组参与谷胱甘肽代谢的酶，以防止运动神经元退化。然而，在星形胶质细胞中，长时间应用成纤维细胞生长因子-1或超氧化物歧化酶介导的氧化应激可能会扰乱正常的神经元-神经胶质细胞相互作用，导致神经元进行性变性。运动神经元中p75神经营养素受体和神经元一氧化氮合酶的重新表达以及反应性星形胶质细胞分泌神经生长因子的增加可能是消除严重损伤神经元的机制之一。因此，星形胶质细胞在ALS中的激活可能具有复杂的致病作用。版权所有(C)2005 S.Karger AG，巴塞尔
Neurons and surrounding glial cells compose a highly specialized functional unit. In amyotrophic lateral sclerosis (ALS) astrocytes interact with motor neurons in a complex manner to modulate neuronal survival. Experiments using chimeric mice expressing ALS-linked mutations to Cu,Zn superoxide dismutase (SOD-1) suggest a critical modulation exerted by neighboring non-neuronal cell types on disease phenotype. When perturbed by primary neuronal damage, e. g. expression of SOD-1 mutations, neurons can signal astrocytes to proliferate and become reactive. Fibroblast growth factor-1 (FGF-1) can be released by motor neurons in response to damage to induce astrocyte activation by signaling through the receptor FGFR1. FGF-1 stimulates nerve growth factor (NGF) expression and secretion, as well as activity of the nuclear factor erythroid 2-related factor 2 (Nrf2) transcription factor. Nrf2 leads to the expression of antioxidant and cytoprotective enzymes such as heme oxygenase-1 and a group of enzymes involved in glutathione metabolism that prevent motor neuron degeneration. However, prolonged stimulation with FGF-1 or SOD-mediated oxidative stress in astrocytes may disrupt the normal neuron-glia interactions and lead to progressive neuronal degeneration. The re-expression of p75 neurotrophin receptor and neuronal NOS in motor neurons in parallel with increased NGF secretion by reactive astrocytes may be a mechanism to eliminate critically damaged neurons. Consequently, astrocyte activation in ALS may have a complex pathogenic role. Copyright (C) 2005 S. Karger AG, Basel