PUBLICATION
Sodium valproate increases activity of the sirtuin pathway resulting in beneficial effects for spinocerebellar ataxia-3 in vivo
- Authors
- Watchon, M., Luu, L., Robinson, K.J., Yuan, K.C., De Luca, A., Suddull, H.J., Tym, M.C., Guillemin, G.J., Cole, N.J., Nicholson, G.A., Chung, R.S., Lee, A., Laird, A.S.
- ID
- ZDB-PUB-210822-1
- Date
- 2021
- Source
- Molecular brain 14: 128 (Journal)
- Registered Authors
- Chung, Roger, Cole, Nicholas, Laird, Angela, Luu, Luan, Watchon, Maxinne, Yuan, Kristy
- Keywords
- Machado?Joseph disease, Neurodegeneration, Polyglutamine, Sodium valproate, Spinocerebellar ataxia?3, Valproic acid, Zebrafish
- MeSH Terms
-
- Peptides/genetics
- Drug Evaluation, Preclinical
- Trinucleotide Repeat Expansion
- Autophagy/drug effects
- Sirtuins/drug effects*
- Sirtuins/physiology
- Drug Synergism
- Animals
- Ataxin-3/antagonists & inhibitors
- Ataxin-3/genetics
- Ataxin-3/metabolism
- Humans
- Zebrafish
- Valproic Acid/pharmacology
- Valproic Acid/therapeutic use*
- Zebrafish Proteins/antagonists & inhibitors
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism
- Signal Transduction
- Genes, Reporter
- Protein Processing, Post-Translational
- Swimming
- Resveratrol/pharmacology
- Resveratrol/therapeutic use
- Histone Deacetylase Inhibitors/pharmacology
- Histone Deacetylase Inhibitors/therapeutic use*
- Disease Models, Animal
- Repressor Proteins/genetics
- Repressor Proteins/metabolism
- Acetylation
- Carbazoles/pharmacology
- Carbazoles/therapeutic use
- Animals, Genetically Modified
- Sirtuin 1/physiology
- HEK293 Cells
- Histones/metabolism
- Recombinant Fusion Proteins/genetics
- Recombinant Fusion Proteins/metabolism
- Machado-Joseph Disease/drug therapy*
- PubMed
- 34416891 Full text @ Mol. Brain
Citation
Watchon, M., Luu, L., Robinson, K.J., Yuan, K.C., De Luca, A., Suddull, H.J., Tym, M.C., Guillemin, G.J., Cole, N.J., Nicholson, G.A., Chung, R.S., Lee, A., Laird, A.S. (2021) Sodium valproate increases activity of the sirtuin pathway resulting in beneficial effects for spinocerebellar ataxia-3 in vivo. Molecular brain. 14:128.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping