Evaluation of the effects of the T-type calcium channel enhancer SAK3 in a rat model of TAF1 deficiency.
Evaluation of the effects of the T-type calcium channel enhancer SAK3 in a rat model of TAF1 deficiency.
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T型钙通道增强剂SAK3在TAF1缺乏大鼠模型中的作用评价
DOI：
10.1016/j.nbd.2020.105224
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发表时间：
2021-03
影响因子：
6.1
通讯作者：
Nelson MA
中科院分区：
文献类型：
--
作者：
Dhanalakshmi C;Janakiraman U;Moutal A;Fukunaga K;Khanna R;Nelson MA
TATA盒结合蛋白相关因子1（TAF 1）是TFIID复合物的一部分，在转录起始过程中起关键作用。TAF 1的变体与神经发育障碍有关。之前，我们发现基于CRISPR/Cas9的TAF 1基因编辑破坏了大脑皮层的形态，并钝化了CaV3.1（T型）电压门控钙通道的表达和功能。在此，我们测试了SAK 3（乙基8′-甲基-2 ′，4-二氧代-2-（哌啶-1-基）-2′ H-螺[环戊烷-1，3′-咪唑并[1，2-a]吡啶]-2-烯-3-羧酸酯），一种T型钙通道增强剂，在TAF 1智力残疾（ID）综合征动物模型中的功效。在出生后第3天，对大鼠幼崽进行脑室内（ICV）注射gRNA对照或gRNA-TAFl CRISPR/Cas9病毒。在出生后第21天，向大鼠幼仔给予SAK 3（0.25mg/kg，p.o.）或媒介物14天（即直到出生后第35天），然后进行行为、形态和分子研究。口服施用SAK 3（0.25mg/kg，p.o.）与TAF 1基因编辑相关的运动异常。SAK 3处理防止了TAF 1基因编辑后观察到的皮质神经元和GFAP阳性星形胶质细胞的损失。此外，SAK 3保护细胞免于凋亡。SAK 3还在TAF 1编辑的动物中恢复了脑源性神经营养因子/蛋白激酶B/糖原合成酶激酶3 β（BDNF/AKT/GSK 3 β）信号传导轴。最后，SAK 3使三种GSK 3 β底物- CaV3.1、FOXP 2和CRMP 2的水平标准化。我们得出结论，T型钙通道增强剂SAK 3部分通过刺激BDNF/AKT/GSK 3 β信号通路而有益于对抗TAF 1基因编辑的有害影响。
The TATA-box binding protein associated factor 1 (TAF1) is part of the TFIID complex that plays a key role during the initiation of transcription. Variants of TAF1 are associated with neurodevelopmental disorders. Previously, we found that CRISPR/Cas9 based editing of the TAF1 gene disrupts the morphology of the cerebral cortex and blunts the expression as well as the function of the CaV3.1 (T-type) voltage gated calcium channel. Here, we tested the efficacy of SAK3 (ethyl 8′-methyl-2′, 4-dioxo-2-(piperidin-1-yl)-2′H-spiro [cyclopentane-1, 3′-imidazo [1, 2-a] pyridine]-2-ene-3-carboxylate), a T-type calcium channel enhancer, in an animal model of TAF1 intellectual disability (ID) syndrome. At post-natal day 3, rat pups were subjected to intracerebroventricular (ICV) injection of either gRNA-control or gRNA-TAF1 CRISPR/Cas9 viruses. At post-natal day 21, the rat pups were given SAK3 (0.25 mg/kg, p.o.) or vehicle for 14 days (i.e. till post-natal day 35) and then subjected to behavioral, morphological, and molecular studies. Oral administration of SAK3 (0.25 mg/kg, p.o.) significantly rescued locomotion abnormalities associated with TAF1 gene editing. SAK3 treatment prevented the loss of cortical neurons and GFAP-positive astrocytes observed after TAF1 gene editing. In addition, SAK3 protected cells from apoptosis. SAK3 also restored the Brain-derived neurotrophic factor/protein kinase B/Glycogen Synthase Kinase 3 Beta (BDNF/AKT/GSK3β) signaling axis in TAF1 edited animals. Finally, SAK3 normalized the levels of three GSK3β substrates - CaV3.1, FOXP2, and CRMP2. We conclude that the T-type calcium channel enhancer SAK3 is beneficial against the deleterious effects of TAF1 gene-editing, in part, by stimulating the BDNF/AKT/GSK3β signaling pathway.
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影响因子：
9.8
作者：
Feuk, Lars;Kalervo, Aino;Hannula-Jouppi, Katariina
通讯作者：
Hannula-Jouppi, Katariina
影响因子：
5.3
作者：
Jäkel S;Dimou L
通讯作者：
Dimou L
影响因子：
46.9
作者：
Heck, Dirk;Kowalczyk, Monika S.;Yudovich, David;Belizaire, Roger;Puram, Rishi V.;McConkey, Marie E.;Thielke, Anne;Aster, Jon C.;Regev, Aviv;Ebert, Benjamin L.
通讯作者：
Ebert, Benjamin L.
影响因子：
4.6
作者：
Gudmundsson, Sanna;Wilbe, Maria;Bondeson, Marie-Louise
通讯作者：
Bondeson, Marie-Louise
TAF1 基因编辑改变小脑和大脑皮层的形态和功能。
影响因子：
6.1
作者：
Janakiraman, Udaiyappan;Yu, Jie;Nelson, Mark A.
通讯作者：
Nelson, Mark A.