Therapeutic relevance of mTOR inhibition in murine succinate semialdehyde dehydrogenase deficiency (SSADHD), a disorder of GABA metabolism.
Therapeutic relevance of mTOR inhibition in murine succinate semialdehyde dehydrogenase deficiency (SSADHD), a disorder of GABA metabolism.
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mTOR 抑制对鼠琥珀酸半醛脱氢酶缺乏症 (SSADHD)（一种 GABA 代谢紊乱）的治疗相关性。
DOI：
10.1016/j.bbadis.2016.10.009
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发表时间：
2017
期刊：
影响因子：
--
通讯作者：
Gibson,KM
中科院分区：
文献类型：
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作者：
Vogel,KR;Ainslie,GR;Jansen,EEW;Salomons,GS;Gibson,KM
醛脱氢酶5a 1缺陷（aldh 5a 1 −/−）小鼠是人类琥珀酸半醛脱氢酶缺陷（SSADHD）的小鼠直向同源物，表现出GABA（4-氨基丁酸）增加，破坏自噬，增加线粒体数量，并诱导氧化应激，所有这些都可以用mTOR（雷帕霉素的机制靶点）抑制剂雷帕霉素缓解[1]。由于GABA调节mTOR，我们测试了这样的假设：aldh 5a 1-/-小鼠将显示与mTOR信号传导和氧化应激相关的基因的mRNA水平发生改变，而这种改变可以通过抑制mTOR来缓解。我们观察到与GABA代谢（γ-羟基丁酸、琥珀酸半醛、D-2-羟基戊二酸、4，5-二氢己酸）和氧化应激相关的多种代谢物在来自dh 5a 1 −/−小鼠的多种组织中显著增加。这些代谢紊乱与aldh 5a 1 −/−小鼠大脑和肝脏中还原型谷胱甘肽（GSH）水平降低以及脂质过氧化副产物4-羟基-2-壬烯醛（4-HNE）加合物水平升高有关。在aldh 5a 1 −/−小鼠中检测到与mTOR信号传导和氧化应激参数相关的多个基因的肝脏mRNA水平降低，并且在给予mTOR抑制剂（Torin 1/Torin 2）后，有几个基因得到了显著改善。Western印迹分析选定的蛋白质对应的氧化应激转录（谷胱甘肽转移酶，超氧化物歧化酶，peroxiredoxin 1）证实了基因表达的结果。我们的数据为mTOR抑制剂在SSADHD中的潜在治疗效果提供了额外的临床前证据。
Aldehyde dehydrogenase 5a1-deficient (aldh5a1−/−) mice, the murine orthologue of human succinic semialdehyde dehydrogenase deficiency (SSADHD), manifest increased GABA (4-aminobutyric acid) that disrupts autophagy, increases mitochondria number, and induces oxidative stress, all mitigated with the mTOR (mechanistic target of rapamycin) inhibitor rapamycin [1]. Because GABA regulates mTOR, we tested the hypothesis thataldh5a1−/−mice would show altered levels of mRNA for genes associated with mTOR signaling and oxidative stress that could be mitigated by inhibiting mTOR. We observed that multiple metabolites associated with GABA metabolism (γ-hydroxybutyrate, succinic semialdehyde, D-2-hydroxyglutarate, 4,5-dihydrohexanoate) and oxidative stress were significantly increased in multiple tissues derived fromaldh5a1−/−mice. These metabolic perturbations were associated with decreased levels of reduced glutathione (GSH) in brain and liver ofaldh5a1−/−mice, as well as increased levels of adducts of the lipid peroxidation by-product, 4-hydroxy-2-nonenal (4-HNE). Decreased liver mRNA levels for multiple genes associated with mTOR signaling and oxidative stress parameters were detected inaldh5a1−/−mice, and several were significantly improved with the administration of mTOR inhibitors (Torin 1/Torin 2). Western blot analysis of selected proteins corresponding to oxidative stress transcripts (glutathione transferase, superoxide dismutase, peroxiredoxin 1) confirmed gene expression findings. Our data provide additional preclinical evidence for the potential therapeutic efficacy of mTOR inhibitors in SSADHD.