mTOR inhibitors rescue premature lethality and attenuate dysregulation of GABAergic/glutamatergic transcription in murine succinate semialdehyde dehydrogenase deficiency (SSADHD), a disorder of GABA metabolism.
mTOR inhibitors rescue premature lethality and attenuate dysregulation of GABAergic/glutamatergic transcription in murine succinate semialdehyde dehydrogenase deficiency (SSADHD), a disorder of GABA metabolism.
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DOI：
10.1007/s10545-016-9959-4
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发表时间：
2016-11
影响因子：
4.2
通讯作者：
Gibson, K. Michael
中科院分区：
文献类型：
--
作者：
Vogel, Kara R.;Ainslie, Garrett R.;Gibson, K. Michael
最近的研究已经确定了超生理GABA在调节mTOR（雷帕霉素的机制靶点）中的作用，mTOR是一种在细胞发育和稳态中具有多效性作用的蛋白激酶，包括生长因子和营养感测的整合以及神经元中的突触输入。乙醛脱氢酶5a 1缺陷（aldh 5a 1 −/−）小鼠，人类琥珀酸半醛脱氢酶缺陷（SSADHD）的小鼠直系同源物，表现出GABA增加，破坏线粒体自噬并增加线粒体数量，同时增强氧化应激。用mTOR抑制剂雷帕霉素治疗可显著减弱这些GABA相关异常。我们通过在aldh 5a 1 −/−小鼠中表征其他雷帕霉素药物，包括替西罗莫司，双重mTOR抑制剂（Torin 1和2（Tor 1/ Tor 2），Ku-0063794和XL-765）以及mTOR非依赖性自噬诱导剂（海藻糖，tat-Beclin 1，FK-506和NF-449）来扩展这些研究。雷帕霉素、Tor 1和Tor 2将这些小鼠从与癫痫持续状态相关的过早死亡中解救出来。XL-765显著延长了aldh 5a 1 −/−小鼠的寿命，并诱导体重增加;未经治疗的aldh 5a 1 −/−小鼠无法增加体重。用Tor 1/Tor 2和XL-765拯救的动物的表达谱显示了GABA能和谷氨酸能受体、GABA/谷氨酸转运蛋白和GABA/谷氨酸相关蛋白的药理学补偿和/或校正的多个实例，Tor 2和XL-765显示出最佳结果。我们的研究为在aldh 5a 1 −/−小鼠中进一步评估mTOR抑制剂奠定了基础，对GABA和谷氨酸神经传递的遗传性疾病具有治疗作用。
Recent studies have identified a role for supraphysiological GABA in the regulation of mTOR (mechanistic target of rapamycin), a protein kinase with pleiotropic roles in cellular development and homeostasis, including integration of growth factors and nutrient sensing, and synaptic input in neurons. Aldehyde dehydrogenase 5a1-deficient (aldh5a1−/−) mice, the murine orthologue of human succinic semialdehyde dehydrogenase deficiency (SSADHD), manifest increased GABA that disrupts mitophagy and increases mitochondria number with enhanced oxidant stress. Treatment with the mTOR inhibitor, rapamycin, significantly attenuates these GABA-related anomalies. We extend those studies through characterization of additional rapalog agents including temsirolimus, dual mTOR inhibitors (torin 1 and 2 (Tor1/ Tor 2), Ku-0063794, and XL-765), as well as mTOR-independent autophagy inducers (trehalose, tat-Beclin 1, FK-506, and NF-449) in aldh5a1−/− mice. Rapamycin, Tor1, and Tor2 rescued these mice from premature lethality associated with status epilepticus. XL-765 extended lifespan significantly and induced weight gain in aldh5a1−/− mice; untreated aldh5a1−/− mice fail to increase body mass. Expression profiling of animals rescued with Tor1/Tor2 and XL-765 revealed multiple instances of pharmacological compensation and/or correction of GABAergic and glutamatergic receptors, GABA/glutamate transporters, and GABA/glutamate-associated proteins, with Tor2 and XL-765 showing optimal outcomes. Our studies lay the groundwork for further evaluation of mTOR inhibitors in aldh5a1−/− mice, with therapeutic ramifications for heritable disorders of GABA and glutamate neurotransmission.
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影响因子：
3.7
作者：
Errington AC;Gibson KM;Crunelli V;Cope DW
通讯作者：
Cope DW
影响因子：
4.2
作者：
Drasbek, K. R.;Vardya, I.;Delenclos, M.;Gibson, K. M.;Jensen, K.
通讯作者：
Jensen, K.
影响因子：
30.8
作者：
Hogema, BM;Gupta, M;Gibson, KM
通讯作者：
Gibson, KM
影响因子：
5
作者：
Rosenberg, Stephen A.;Niglio, Scot A.;Salehomoum, Negar;Chan, Joseph L. -K.;Jeong, Byeong-Seon;Wen, Yu;Li, Jiadong;Fukui, Jami;Chen, Suzie;Shin, Seung-Shick;Goydos, James S.
通讯作者：
Goydos, James S.
影响因子：
4.2
作者：
Donarum, EA;Stephan, DA;Gibson, KM
通讯作者：
Gibson, KM