Increased levels of p70S6 phosphorylation in the G93A mouse model of Amyotrophic Lateral Sclerosis and in valine-exposed cortical neurons in culture
Increased levels of p70S6 phosphorylation in the G93A mouse model of Amyotrophic Lateral Sclerosis and in valine-exposed cortical neurons in culture
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DOI：
10.1016/j.expneurol.2010.08.033
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发表时间：
2010-11-01
影响因子：
5.3
通讯作者：
Zona, Cristina
中科院分区：
文献类型：
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作者：
Carunchio, Irene;Curcio, Livia;Zona, Cristina
意大利足球运动员中肌萎缩侧索硬化症（ALS）的高风险因素仍然是一个有争议的问题。已经制定的解释ALS和足球运动员之间可能存在联系的假设之一与滥用膳食补充剂和药物以提高运动成绩有关。特别是，据报道，支链氨基酸（BCAA）被广泛用于运动员作为营养补充剂。为了观察支链氨基酸对神经元电特性的可能影响，我们对对照培养的皮层神经元和支链氨基酸处理后的神经元进行了电生理实验。BCAA处理的神经元表现出过度兴奋性，雷帕霉素能够抑制它，并显着降低mTOR，Akt和p70 S6磷酸化的水平。有趣的是，先前报道的来自ALS遗传小鼠模型（G93A）的皮质神经元的超兴奋性也被雷帕霉素治疗逆转。此外，与对照神经元相比，G93A和缬氨酸处理的神经元均呈现显著更高水平的Pp7056，强烈表明该底物参与ALS病理。最后，我们对来自对照和G93A小鼠以及喂食富含BCAA的饮食的小鼠的运动皮层切片进行了电生理实验。我们观察到神经元兴奋性在G93A和富含BCAA的饮食小鼠之间是相当的，但显著高于对照小鼠。这些发现，除了强烈表明支链氨基酸特异性诱导过度兴奋，似乎表明参与ALS病理的p70 S6底物。(C)2010年爱思唯尔公司All rights reserved.
The higher risk factor for Amyotrophic lateral Sclerosis (ALS) among Italian soccer players is a question that is still debated. One of the hypotheses that have been formulated to explain a possible link between ALS and soccer players is related to the abuse of dietary supplements and drugs for enhancing sporting performance. In particular, it has been reported that branched-chain amino acids (BCAAs) are widely used among athletes as nutritional supplements. To observe the possible effect of BCAAs on neuronal electrical properties, we performed electrophysiological experiments on Control cultured cortical neurons and on neurons after BCAA treatment. BCAA-treated neurons showed hyperexcitability and rapamycin was able to suppress it and significantly reduce the level of mTOR, Akt and p70S6 phosphorylation. Interestingly, the hyperexcitability previously reported in cortical neurons from a genetic mouse model of ALS (G93A) was also reversed by rapamycin treatment. Moreover, both G93A and valine-treated neurons presented significantly higher levels of Pp7056 when compared to control neurons, strongly indicating the involvement of this substrate in ALS pathology. Finally, we performed electrophysiological experiments on motor cortex slices from Control and G93A mice and those fed with a BCAA-enriched diet. We observed that neuron excitability was comparable between G93A and BCAA-enriched diet mice, but was significantly higher than in Control mice. These findings, besides strongly indicating that BCAAs specifically induce hyperexcitability, seem to suggest the involvement of p70S6 substrate in ALS pathology. (C) 2010 Elsevier Inc. All rights reserved.