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
Highlights
Machado-Joseph disease (MJD), known as spinocerebellar ataxia type 3, is a fatal neurodegenerative disease characterized by clinical symptoms including ataxia, dystonia, rigidity, muscle atrophy, and visual and speech disorder [10, 33, 36]
Probing the immunoblots for acetylated histone 3 and histone 4 revealed a decrease in both with increasing ataxin-3 polyQ length (Fig. 1A), with significantly decreased levels of both ac-H3K9 and ac-H4K5 in enhanced green fluorescent protein (EGFP)-Ataxin-3 84Q larvae compared to non-transgenic animals (Fig. 1B-C)
Here we demonstrate that histone acetylation, which plays a role in transcription regulation, is altered in transgenic MJD zebrafish expressing human ataxin-3 with expanded polyQ tract
Summary
Machado-Joseph disease (MJD), known as spinocerebellar ataxia type 3, is a fatal neurodegenerative disease characterized by clinical symptoms including ataxia, dystonia, rigidity, muscle atrophy, and visual and speech disorder [10, 33, 36]. B Quantification of ac-H3K9 showed wild-type and mutant ataxin-3 larvae with significantly lower levels of ac-H3K9 compared to the non-transgenic control (*p < 0.022, n = 3–5). C Densitometric analysis of the amount of ac-H4K5 revealed a significant decrease in ac-H4K5 in the mutant ataxin-3 zebrafish compared to the non-transgenic control (*p = 0.026, n = 3–5). D Treatment of MJD zebrafish with low-dose sodium valproate (valproate; 3.125 μM) increased the distance travelled during movement tracking to control treated EGFP-Ataxin-3 84Q (^p = 0.019, n = 93–161). H Quantification of human FL ataxin-3 showed significantly increased levels with both concentrations of valproate treatment compared to vehicle treated mutant ataxin-3 fish (*p = 0.0495, **p = 0.002, n = 5–11). I Quantification of human CF ataxin-3 relative to loading control showed no changes after treatment with sodium valproate (n = 3–6). Statistical analysis used in this figure were paired and unpaired one-way ANOVA with Tukey post-hoc analysis expanded CAG repeat within the ATXN3 gene results in presence of a long polyglutamine (polyQ) tract towards the C-terminus of the ataxin-3 protein [27, 28]
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