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Treatment with sodium butyrate has therapeutic benefits for Machado-Joseph disease through the induction of autophagy

ABSTRACT: 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.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Permanent Cell Line Cell, Cell Culture

SUBMITTER: Albert Lee

LAB HEAD: Albert Lee

PROVIDER: PXD024626 | Pride | 2024-01-24

REPOSITORIES: Pride

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Treatment with sodium butyrate induces autophagy resulting in therapeutic benefits for spinocerebellar ataxia type 3.

Watchon Maxinne M Robinson Katherine J KJ Luu Luan L An Yousun Y Yuan Kristy C KC Plenderleith Stuart K SK Cheng Flora F Don Emily K EK Nicholson Garth A GA Lee Albert A Laird Angela S AS

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20240101 2

Spinocerebellar ataxia type 3 (SCA3, also known as Machado Joseph disease) is a fatal neurodegenerative disease caused by the expansion of the trinucleotide repeat region within the ATXN3/MJD gene. Mutation of ATXN3 causes formation of 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- ...[more]

PMID: 38258931

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Project description:Background: SH-SY5Y cells exhibit a neuronal phenotype when treated with all-trans retinoic acid (RA), but the molecular mechanism of activation in the signaling pathway mediated by phosphatidylinositol 3-kinase (PI3K) is not sufficiently understood. To shed new light on the mechanism, we comprehensively compared the gene expression profiles between SK-N-SH cells and two subtypes of SH-SY5Y cells (SH-SY5Y-A and SH-SY5Y-E), each of which showed a different phenotype during RA-mediated differentiation. Results: SH-SY5Y-A cells differentiated in the presence of RA, whereas RA-treated SH-SY5Y-E cells required additional treatment with brain-derived neurotrophic factor (BDNF) for full differentiation. In combination with perturbation using a PI3K inhibitor, LY294002, we identified 386 genes and categorized them into two clusters dependent on the PI3K signaling pathway during RA-mediated differentiation in SH-SY5Y-A cells. Transcriptional regulation of the gene cluster was greatly reduced in SK-N-SH cells or partially impaired in SH-SY5Y-E cells in coincidence with a defect in the neuronal phenotype of these cell lines. Additional stimulation with BDNF induced a set of neural genes which were down-regulated in RA-treated SH-SY5Y-E cells but were abundant in the differentiated SH-SY5Y-A cells. Conclusions: We identified the gene clusters controlled by PI3K- and TRKB-mediated signaling pathways during differentiation in two subtypes of SH-SY5Y cells. TRKB-mediated bypass pathway compensates for the impaired neural functions generated by defects in several signaling pathways including PI3K in SH-SY5Y-E cells. The expression profiling data are useful for further studies to elucidate the signal transduction-transcriptional network including PI3K and/or TRKB. Experiment Overall Design: Human neuroblastomas, SK-N-SH (HTB-11) and SH-SY5Y-A cells (CRL-2266) were obtained from the American Type Culture Collection (ATCC). We also obtained SH-SY5Y-E cells (EC94030304) from the European Collection of Cell Cultures (ECACC). Tissue culture cells were maintained in D-MEM/F12 1:1 mixture supplemented with 15% FBS (Fetal Bovine Serum) and 1% NEAA (Non-essential amino acid) in a 5% CO2 humidified incubator at 37oC. The culture medium was changed twice a week. For the RA-inducible experiment, random culture cells from two clone subtypes of SH-SY5Y and SK-N-SH were seeded in laminin coated culture dishes (BioCoat Laminin Cellware; BD Biosciences, Billerica, MA, USA) for 1 day and then transferred to a medium containing 10 μM of RA in the presence or the absence of LY294002 (10μM) for five days. For BDNF-induced sequential differentiation of the SH-SY5Y-E strain, cells were washed with D-MEM/F12 twice after five days in the presence of RA and then incubated with 50 ng/ml of BDNF in D-MEM/F12 without serum for three days.

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