Dataset Information

Sodium valproate is protective in a transgenic zebrafish model of Machado Joseph disease

ABSTRACT: The neurodegenerative disease Machado Joseph disease (MJD, also known as spinocerebellar ataxia-3) is a fatal disease that impairs control and co-ordination of movement. MJD is caused by expansion of a trinucleotide (CAG) repeat region within the ATXN3 gene, encoding a long polyglutamine (polyQ) region within the ataxin-3 protein. As transcription regulation is one of the functions of the ataxin-3 protein, weWe aimed to examine whether zebrafish expressing polyQ expanded ataxin-3 had altered levels of histone acetylation, and to establish test whether treatment with the histone deacetylase (HDAC) inhibitor sodium valproate was protective for the the first transgenic zebrafish.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Danio Rerio (zebrafish) (brachydanio Rerio)

TISSUE(S): Embryo

DISEASE(S): Machado-joseph Disease

SUBMITTER: Albert Lee

LAB HEAD: Albert Lee

PROVIDER: PXD009612 | Pride | 2021-08-23

REPOSITORIES: Pride

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Publications

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

Watchon Maxinne M Luu Luan L Robinson Katherine J KJ Yuan Kristy C KC De Luca Alana A Suddull Hannah J HJ Tym Madelaine C MC Guillemin Gilles J GJ Cole Nicholas J NJ Nicholson Garth A GA Chung Roger S RS Lee Albert A Laird Angela S AS

Molecular brain 20210820 1

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 ...[more]

PMID: 34416891

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Project description:Machado-Joseph disease (MJD) is a fatal neurodegenerative disease caused by expansion of the trinucleotide repeat region within the ATXN3/MJD gene. Mutation of ATXN3 causes formation of neurotoxic ataxin-3 protein aggregates, neurodegeneration and motor deficits. Here we investigated the therapeutic potential and mechanistic activity of sodium butyrate (SB), the sodium salt of butyric acid, a metabolite naturally produced by gut microbiota, on cultured SH-SY5Y cells and transgenic zebrafish expressing human ataxin-3 containing 84 glutamine (Q) residues to model MJD. MJD SH-SY5Y cells were found to contain ataxin-3 oligomeric species and protein aggregates. Treatment with SB increased activity of the autophagy protein quality control pathway in the MJD cells, decreased presence of ataxin-3 aggregates and presence of ataxin-3 oligomers in an autophagy-dependent manner. Treatment with SB was also beneficial in vivo, improving swimming performance, increasing autophagy activity and decreasing presence of insoluble ataxin-3 protein species in the transgenic MJD zebrafish. Co-treating the MJD zebrafish with SB and chloroquine, an autophagy inhibitor, prevented the beneficial effects of SB on the zebrafish swimming, suggesting that the improved swimming performance was autophagy-dependent. To identify mechanism of the induction of autophagy by SB, we performed proteomic analysis of protein lysates from the SB treated and untreated MJD SH-SY5Y cells. We found that SB treatment had increased activity of Protein Kinase A and AMPK signaling. Immunoblot analysis confirmed that SB treatment had increased levels of acetylated FOXO1 protein. Further, co-treatment with an inhibitor of FOXO1 transcriptional activity (AS1842856) prevented the increase in autophagosome formation (LC3II/I) usually produced by SB treatment. Together our findings indicate that treatment with SB can increase activity of the autophagy pathway through a FOXO1-dependent process and that this has beneficial effects in vitro and in vivo. We propose that treatment with sodium butyrate warrants further investigation for the treatment of neurodegenerative diseases underpinned by proteinopathy mechanisms, including MJD.

Dataset Information

Sodium valproate is protective in a transgenic zebrafish model of Machado Joseph disease

Publications

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

Similar Datasets

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