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Sodium valproate increases activity of the sirtuin pathway resulting in beneficial effects for spinocerebellar ataxia-3 in vivo
Molecular Brain ( IF 3.6 ) Pub Date : 2021-08-20 , DOI: 10.1186/s13041-021-00839-x
Maxinne Watchon 1 , Luan Luu 1 , Katherine J Robinson 1 , Kristy C Yuan 1 , Alana De Luca 1 , Hannah J Suddull 1 , Madelaine C Tym 1 , Gilles J Guillemin 1 , Nicholas J Cole 1 , Garth A Nicholson 1, 2 , Roger S Chung 1 , Albert Lee 1 , Angela S Laird 1
Affiliation  

Machado-Joseph disease (MJD, also known as spinocerebellar ataxia type 3) is a fatal neurodegenerative disease that impairs control and coordination of movement. Here we tested whether treatment with the histone deacetylase inhibitor sodium valproate (valproate) prevented a movement phenotype that develops in larvae of a transgenic zebrafish model of the disease. We found that treatment with valproate improved the swimming of the MJD zebrafish, affected levels of acetylated histones 3 and 4, but also increased expression of polyglutamine expanded human ataxin-3. Proteomic analysis of protein lysates generated from the treated and untreated MJD zebrafish also predicted that valproate treatment had activated the sirtuin longevity signaling pathway and this was confirmed by findings of increased SIRT1 protein levels and sirtuin activity in valproate treated MJD zebrafish and HEK293 cells expressing ataxin-3 84Q, respectively. Treatment with resveratrol (another compound known to activate the sirtuin pathway), also improved swimming in the MJD zebrafish. Co-treatment with valproate alongside EX527, a SIRT1 activity inhibitor, prevented induction of autophagy by valproate and the beneficial effects of valproate on the movement in the MJD zebrafish, supporting that they were both dependent on sirtuin activity. These findings provide the first evidence of sodium valproate inducing activation of the sirtuin pathway. Further, they indicate that drugs that target the sirtuin pathway, including sodium valproate and resveratrol, warrant further investigation for the treatment of MJD and related neurodegenerative diseases.

中文翻译:

丙戊酸钠增加sirtuin通路的活性,对体内脊髓小脑性共济失调3产生有益作用

Machado-Joseph 病(MJD,也称为 3 型脊髓小脑性共济失调)是一种致命的神经退行性疾病,会损害运动的控制和协调。在这里,我们测试了组蛋白去乙酰化酶抑制剂丙戊酸钠 (丙戊酸钠) 的治疗是否阻止了在该病的转基因斑马鱼模型的幼虫中发育的运动表型。我们发现丙戊酸盐治疗改善了 MJD 斑马鱼的游泳能力,影响了乙酰化组蛋白 3 和 4 的水平,但也增加了多聚谷氨酰胺扩增的人类 ataxin-3 的表达。对经处理和未经处理的 MJD 斑马鱼产生的蛋白质裂解物的蛋白质组学分析还预测,丙戊酸盐处理激活了 sirtuin 长寿信号通路,这一点通过丙戊酸盐处理的 MJD 斑马鱼和表达 ataxin-的 HEK293 细胞中 SIRT1 蛋白水平和 sirtuin 活性增加的结果得到证实。 3 84Q,分别。用白藜芦醇(另一种已知可激活去乙酰化酶途径的化合物)治疗,也改善了 MJD 斑马鱼的游泳能力。与丙戊酸盐和 EX527(一种 SIRT1 活性抑制剂)共同治疗,可防止丙戊酸盐诱导自噬以及丙戊酸盐对 MJD 斑马鱼运动的有益作用,支持它们都依赖于 sirtuin 活性。这些发现提供了丙戊酸钠诱导sirtuin途径激活的第一个证据。此外,他们还指出,针对去乙酰化酶途径的药物,包括丙戊酸钠和白藜芦醇,值得进一步研究用于治疗 MJD 和相关的神经退行性疾病。
更新日期:2021-08-20
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