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首页> 外文期刊>Current Biology: CB >Decreasing glutamate buffering capacity triggers oxidative stress and neuropil degeneration in the Drosophila brain
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Decreasing glutamate buffering capacity triggers oxidative stress and neuropil degeneration in the Drosophila brain

机译：降低谷氨酸的缓冲能力会触发果蝇大脑中的氧化应激和神经纤维变性

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摘要

L-glutamate is both the major brain excitatory neurotransmitter [1, 2] and a potent neurotoxin [3,4] in mammals. Glutamate excitotoxicity is partly responsible for cerebral traumas evoked by ischemia [5, 6] and has been implicated in several neurodegenerative diseases including amyotrophic lateral sclerosis (ALS) [7-9]. In contrast, very little is known about the function or potential toxicity of glutamate in the insect brain. Here, we show that decreasing glutamate buffering capacity is neurotoxic in Drosophila. We found that the only Drosophila high-affinity glutamate transporter, dEAAT1 [10-13], is selectively addressed to glial extensions that project ubiquitously through the neuropil close to synaptic areas. Inactivation of dEAAT1 by RNA interference led to characteristic behavior deficits that were significantly rescued by expression of the human glutamate transporter hEAAT2 or the administration in food of riluzole, an anti-excitotoxic agent used in the clinic for human ALS patients. Signs of oxidative stress included hypersensitivity to the free radical generator paraquat and rescue by the antioxidant melatonin. Inactivation of dEAAT1 also resulted in shortened lifespan and marked brain neuropil degeneration characterized by widespread microvacuolization and swollen mitochondria. This suggests that the dEAAT1-deficient fly provides a powerful genetic model system for molecular analysis of glutamate-mediated neurodegeneration.
机译：谷氨酸在哺乳动物中既是主要的大脑兴奋性神经递质[1，2]，又是有效的神经毒素[3,4]。谷氨酸兴奋性毒性是局部缺血引起的脑损伤的部分原因[5，6]，并与包括肌萎缩性侧索硬化症（ALS）[7-9]在内的多种神经退行性疾病有关。相反，关于谷氨酸在昆虫脑中的功能或潜在毒性知之甚少。在这里，我们表明，降低果氨酸的缓冲能力在果蝇中具有神经毒性。我们发现，唯一的果蝇高亲和力谷氨酸转运蛋白，dEAAT1 [10-13]，选择性地针对了神经胶质延伸，这些延伸无处不在地通过突触区域附近的神经桩投射。 RNA干扰使dEAAT1失活导致特征性行为缺陷，这种缺陷可通过人谷氨酸转运蛋白hEAAT2的表达或利鲁唑（一种用于人类ALS患者临床的抗兴奋剂）在食物中的使用而得到明显缓解。氧化应激的迹象包括对自由基产生剂百草枯的超敏反应和抗氧化剂褪黑素的拯救。 dEAAT1的失活还导致寿命缩短和明显的脑神经纤维变性，其特征是广泛的微真空化和线粒体肿胀。这表明缺乏dEAAT1的果蝇为谷氨酸介导的神经变性的分子分析提供了强大的遗传模型系统。

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