Notch pathway is activated in cell culture and mouse models of mutant SOD1-related familial amyotrophic lateral sclerosis, with suppression of its activation as an additional mechanism of neuroprotection for lithium and valproate
Notch pathway is activated in cell culture and mouse models of mutant SOD1-related familial amyotrophic lateral sclerosis, with suppression of its activation as an additional mechanism of neuroprotection for lithium and valproate
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Notch 通路在突变型 SOD1 相关家族性肌萎缩侧索硬化症的细胞培养物和小鼠模型中被激活，抑制其激活是锂和丙戊酸盐的神经保护的额外机制
DOI：
10.1016/j.neuroscience.2015.06.002
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发表时间：
2015-08
期刊：
影响因子：
3.3
通讯作者：
H.-L. Feng
中科院分区：
文献类型：
--
作者：
G.-T. Dong;T.-H. Wang;Y.-Q. Yang;H.-L. Feng
肌萎缩性侧索硬化症（ALS）是一种特发性致死性神经退行性疾病，目前尚无有效的治疗方法。最近的一项研究发现，在ALS的果蝇模型中，Notch信号通路上调。Notch信号在中枢神经系统中起着主要的调节作用。然而，Notch参与ALS发病的机制尚未完全阐明。最近的研究表明，情绪稳定剂锂和丙戊酸（VPA）能够调节Notch信号。我们的研究旨在证实Notch通路与ALS之间的关系，以及Notch通路是否参与了锂和VPA对ALS的神经保护作用。我们发现Notch通路在vitroandin的ALS模型中被激活，并且Notch信号抑制剂N-[N-(3,5-二氟苯乙酰- l- alanyl)]- s -苯基甘氨酸t-丁基酯（DAPT）和Notch1 siRNA抑制Notch激活可显著减少神经元凋亡信号。Bcl-2的上调以及Bax和细胞色素c的下调证明了这一点。我们还发现锂和VPA抑制了与超氧化物歧化酶-1 （SOD1）突变相关的Notch激活，并且锂和VPA联合使用比单独使用任何一种药物产生更强大的作用。我们的研究结果表明，Notch通路在ALS中起着关键作用，锂和VPA对突变型sod1介导的神经元损伤的神经保护作用至少部分依赖于它们对Notch激活的抑制。
Amyotrophic lateral sclerosis (ALS) is an idiopathic and lethal neurodegenerative disease that currently has no effective treatment. A recent study found that the Notch signaling pathway was up-regulated in a TAR DNA-binding protein-43 (TDP-43)Drosophilamodel of ALS. Notch signaling acts as a master regulator in the central nervous system. However, the mechanisms by which Notch participates in the pathogenesis of ALS have not been completely elucidated. Recent studies have shown that the mood stabilizers lithium and valproic acid (VPA) are able to regulate Notch signaling. Our study sought to confirm the relationship between the Notch pathway and ALS and whether the Notch pathway contributes to the neuroprotective effects of lithium and VPA in ALS. We found that the Notch pathway was activated inin vitroandin vivomodels of ALS, and suppression of Notch activation with a Notch signaling inhibitor, N-[N-(3,5-difluorophenacetyl-L-alanyl)]-S-phenylglycine t-butyl ester (DAPT) and Notch1 siRNA significantly reduced neuronal apoptotic signaling, as evidenced by the up-regulation of Bcl-2 as well as the down-regulation of Bax and cytochrome c. We also found that lithium and VPA suppressed the Notch activation associated with the superoxide dismutase-1 (SOD1) mutation, and the combination of lithium and VPA produced a more robust effect than either agent alone. Our findings indicate that the Notch pathway plays a critical role in ALS, and the neuroprotective effects of lithium and VPA against mutant SOD1-mediated neuronal damage are at least partially dependent on their suppression of Notch activation.
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肌萎缩性侧硬化症。
DOI：
10.1016/s0140-6736(22)01272-7
发表时间：
2022-10-15
期刊：
Lancet (London, England)
影响因子：
--
作者：
通讯作者：
--
影响因子：
3.3
作者：
Umka, J.;Mustafa, S.;Wigmore, P. M.
通讯作者：
Wigmore, P. M.
影响因子：
64.8
作者：
Brian M. Owens
通讯作者：
Brian M. Owens
影响因子：
64.8
作者：
RUEL, L;BOUROUIS, M;SIMPSON, P
通讯作者：
SIMPSON, P
影响因子：
9
作者：
Greenblatt, David Yu;Cayo, Max A.;Chen, Herbert
通讯作者：
Chen, Herbert