Sodium valproate increases activity of the sirtuin pathway resulting in beneficial effects for spinocerebellar ataxia-3 in vivo

Molecular Brain

Garth A. Nicholson¹  Roger S. Chung¹  Angela S. Laird¹  Alana De Luca¹  Katherine J. Robinson¹  Gilles J. Guillemin¹  Kristy C. Yuan¹  Maxinne Watchon¹  Luan Luu¹  Nicholas J. Cole¹  Hannah J. Suddull¹  Albert Lee¹  Madelaine C. Tym¹ 

[1] Centre for Motor Neuron Disease Research, Department of Biomedical Sciences, Faculty of Medicine, Health and Human Sciences, Macquarie University;

关键词: Machado−Joseph disease;    Spinocerebellar ataxia−3;    Zebrafish;    Neurodegeneration;    Sodium valproate;    Valproic acid;   

DOI  :  10.1186/s13041-021-00839-x

来源: DOAJ

【 摘 要 】

Abstract 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. Graphical abstract

【 授权许可】

Unknown