In vitro modeling of experimental succinic semialdehyde dehydrogenase deficiency (SSADHD) using brain-derived neural stem cells.
In vitro modeling of experimental succinic semialdehyde dehydrogenase deficiency (SSADHD) using brain-derived neural stem cells.
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DOI：
10.1371/journal.pone.0186919
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Gibson KM
中科院分区：
文献类型：
--
作者：
Vogel KR;Ainslie GR;Jansen EE;Salomons GS;Roullet JB;Gibson KM
我们探讨了神经干细胞（NSCs）作为体外模型的效用，用于评估琥珀酸半醛脱氢酶缺陷（SSADHD）小鼠的临床前治疗。从aldh 5a 1 +/+和aldh 5a 1-/-小鼠（aldh 5a 1 =醛脱氢酶5a 1 = SSADH）获得NSC。评价了多个参数，包括：（1）GHB的产量（2）用双重mTOR从细胞死亡中拯救;（雷帕霉素的机制靶点）抑制剂XL-765，一种先前显示可拯救aldh 5a 1-/-小鼠免于过早致死的药剂;（3）线粒体数量、总活性氧和线粒体超氧化物产生，这些都是先前在aldh 5a 1-/-小鼠中被记录为异常的;和（5）与癫痫相关的选定基因表达谱，这是实验性和人类SSADHD的突出特征。在所有这些参数中观察到功能障碍的模式，并反映了aldh 5a 1-/-小鼠中的早期发现。下丘脑和神经干细胞之间以离子通道、GABA能受体和炎症为中心的基因表达失调的模式，提示了新的病理机制以及与小鼠癫痫表型潜在相关的基因表达的发育个体发生。SSADHD的NSC模型将在提供中枢作用疗法的第一层筛选和优先考虑适用于SSADHD的临床前动物研究的治疗概念方面具有价值。
We explored the utility of neural stem cells (NSCs) as an in vitro model for evaluating preclinical therapeutics in succinic semialdehyde dehydrogenase-deficient (SSADHD) mice. NSCs were obtained from aldh5a1+/+ and aldh5a1-/- mice (aldh5a1 = aldehyde dehydrogenase 5a1 = SSADH). Multiple parameters were evaluated including: (1) production of GHB (γ-hydroxybutyrate), the biochemical hallmark of SSADHD; (2) rescue from cell death with the dual mTOR (mechanistic target of rapamycin) inhibitor, XL-765, an agent previously shown to rescue aldh5a1-/- mice from premature lethality; (3) mitochondrial number, total reactive oxygen species, and mitochondrial superoxide production, all previously documented as abnormal in aldh5a1-/- mice; (4) total ATP levels and ATP consumption; and (5) selected gene expression profiles associated with epilepsy, a prominent feature in both experimental and human SSADHD. Patterns of dysfunction were observed in all of these parameters and mirrored earlier findings in aldh5a1-/- mice. Patterns of dysregulated gene expression between hypothalamus and NSCs centered on ion channels, GABAergic receptors, and inflammation, suggesting novel pathomechanisms as well as a developmental ontogeny for gene expression potentially associated with the murine epileptic phenotype. The NSC model of SSADHD will be valuable in providing a first-tier screen for centrally-acting therapeutics and prioritizing therapeutic concepts of preclinical animal studies applicable to SSADHD.
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