Inhibition of the glutamine transporter SNAT1 confers neuroprotection in mice by modulating the mTOR-autophagy system
Inhibition of the glutamine transporter SNAT1 confers neuroprotection in mice by modulating the mTOR-autophagy system
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DOI：
10.1038/s42003-019-0582-4
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发表时间：
2019-09
影响因子：
5.9
通讯作者：
D. Yamada;K. Kawabe;Ikue Tosa;Shunpei Tsukamoto;Ryota Nakazato;M. Kou;Koichi Fujikawa;Saki Nakamura-Saki-Nak
中科院分区：
文献类型：
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作者：
D. Yamada;K. Kawabe;Ikue Tosa;Shunpei Tsukamoto;Ryota Nakazato;M. Kou;Koichi Fujikawa;Saki Nakamura-Saki-Nak
哺乳动物雷帕霉素靶点复合物1 （mTORC1）在神经退行性疾病中的病理生理作用已经确定，但其在神经元中激活的可能治疗靶点还有待探索。在这里，我们发现溶质载体家族38a成员1 （SNAT1,Slc38a1）是神经元中mTORC1的正调节因子。Slc38a1flox/floxandSynapsin I-Cremice杂交产生突变小鼠，其中slc38a1在神经元中被选择性地删除。在小鼠大脑中动脉闭塞（MCAO）模型中测量2,3,5-三苯四唑氯（TTC）或map2阴性区域显示，slc38a1缺乏可减小梗死面积。我们发现p70S6k1 （pp70S6k1）磷酸化的短暂增加和雷帕霉素对MCAO小鼠梗死面积的抑制作用。在体外卒中培养条件下，自噬抑制剂完全减轻了SNAT1缺乏对神经元细胞死亡的抑制作用。这些结果表明，SNAT1通过mtor自噬系统促进缺血性脑损伤。
The pathophysiological role of mammalian target of rapamycin complex 1 (mTORC1) in neurodegenerative diseases is established, but possible therapeutic targets responsible for its activation in neurons must be explored. Here we identified solute carrier family 38a member 1 (SNAT1,Slc38a1) as a positive regulator of mTORC1 in neurons.Slc38a1flox/floxandSynapsin I-Cremice were crossed to generate mutant mice in whichSlc38a1was selectively deleted in neurons. Measurement of 2,3,5-triphenyltetrazolium chloride (TTC) or the MAP2-negative area in a mouse model of middle cerebral artery occlusion (MCAO) revealed thatSlc38a1deficiency decreased infarct size. We found a transient increase in the phosphorylation of p70S6k1 (pp70S6k1) and a suppressive effect of rapamycin on infarct size in MCAO mice. Autophagy inhibitors completely mitigated the suppressive effect of SNAT1 deficiency on neuronal cell death under in vitro stroke culture conditions. These results demonstrate that SNAT1 promoted ischemic brain damage via mTOR-autophagy system.