Early interneuron dysfunction in ALS: insights from a mutant sod1 zebrafish model.
Early interneuron dysfunction in ALS: insights from a mutant sod1 zebrafish model.
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DOI：
10.1002/ana.23780
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发表时间：
2013-02
影响因子：
11.2
通讯作者：
Ramesh, Tennore M.
中科院分区：
文献类型：
--
作者：
McGown, Alexander;McDearmid, Jonathan R.;Panagiotaki, Niki;Tong, Huaxia;Al Mashhadi, Sufana;Redhead, Natasha;Lyon, Alison N.;Beattie, Christine E.;Shaw, Pamela J.;Ramesh, Tennore M.
使用转基因突变体sod1斑马鱼模型确定肌萎缩侧索硬化症（ALS）的病理生理学发作的时间、方式和神经元，并鉴定神经保护药物。蛋白质病如ALS涉及错误折叠并激活热休克应激反应（HSR）的突变蛋白。HSR是神经元应激的指示，并且我们在我们的转基因斑马鱼中使用荧光hsp70-DsRed报告子来跟踪神经元应激并测量疾病过程中神经元和肌肉的功能变化。我们发现，突变sod1鱼第一次表现出的HSR在甘氨酸能中间神经元在受精后24小时（hpf）。到96 hpf时，我们观察到脊髓运动神经元中诱导的自发甘氨酸能电流显著减少。抑制的损失，其次是增加压力的运动神经元的症状成人和并发的形态学变化，在神经肌肉接头（NMJ）指示去神经支配。唯一批准的ALS药物阿舒唑和NRF2激活剂阿扑吗啡减少了观察到的早期神经元应激反应。最早的事件中的ALS的病理生理学在突变体sod1斑马鱼模型涉及神经元的应力抑制性interneurons，导致突变体sod1的表达。随后是运动神经元的抑制性输入减少。抑制性输入的丧失可能导致运动神经元中神经元应激的后期发展以及同时无法维持NMJ。已批准用于ALS的药物利鲁唑调节中间神经元中的神经元应激，表明利鲁唑作用的新机制。神经网络2013; 73：246 - 258
To determine, when, how, and which neurons initiate the onset of pathophysiology in amyotrophic lateral sclerosis (ALS) using a transgenic mutant sod1 zebrafish model and identify neuroprotective drugs. Proteinopathies such as ALS involve mutant proteins that misfold and activate the heat shock stress response (HSR). The HSR is indicative of neuronal stress, and we used a fluorescent hsp70-DsRed reporter in our transgenic zebrafish to track neuronal stress and to measure functional changes in neurons and muscle over the course of the disease. We show that mutant sod1 fish first exhibited the HSR in glycinergic interneurons at 24 hours postfertilization (hpf). By 96 hpf, we observed a significant reduction in spontaneous glycinergic currents induced in spinal motor neurons. The loss of inhibition was followed by increased stress in the motor neurons of symptomatic adults and concurrent morphological changes at the neuromuscular junction (NMJ) indicative of denervation. Riluzole, the only approved ALS drug and apomorphine, an NRF2 activator, reduced the observed early neuronal stress response. The earliest event in the pathophysiology of ALS in the mutant sod1 zebrafish model involves neuronal stress in inhibitory interneurons, resulting from mutant Sod1 expression. This is followed by a reduction in inhibitory input to motor neurons. The loss of inhibitory input may contribute to the later development of neuronal stress in motor neurons and concurrent inability to maintain the NMJ. Riluzole, the approved drug for use in ALS, modulates neuronal stress in interneurons, indicating a novel mechanism of riluzole action. ANN NEUROL 2013;73:246–258
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影响因子：
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作者：
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通讯作者：
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通讯作者：
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影响因子：
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通讯作者：
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