PXD024626

PXD024626 is an original dataset announced via ProteomeXchange.

Title	Treatment with sodium butyrate has therapeutic benefits for Machado-Joseph disease through the induction of autophagy
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.
HostingRepository	PRIDE
AnnounceDate	2024-01-24
AnnouncementXML	Submission_2024-01-23_20:09:09.104.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD024626
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Albert Lee
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	acetylated residue; monohydroxylated residue; deamidated residue; iodoacetamide derivatized residue
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2021-03-10 02:19:15	ID requested
⏵ 1	2024-01-23 20:09:10	announced

10.1096/fj.202300963rr;

Watchon M, Robinson KJ, Luu L, An Y, Yuan KC, Plenderleith SK, Cheng F, Don EK, Nicholson GA, Lee A, Laird AS, type 3. FASEB J, 38(2):e23429(2024) [pubmed]

10.6019/PXD024626;

submitter keyword: autophagy, trinucleotide repeat disease, label-free proteomics, Spinocerebellar ataxia 3, flow cytometry, sodium butyrate, microbiota, machado-joseph disease, polyQ, neurodegeneration, zebrafish

Albert Lee
contact affiliation	Centre for MND Research, Department of Biomedical Sciences, Macquarie University, North Ryde, NSW Australia
contact email	albert.lee@mq.edu.au
lab head
Albert Lee
contact affiliation	Macquarie University
contact email	albert.lee@mq.edu.au
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD024626
     1. Label: PRIDE project
     2. Name: Treatment with sodium butyrate has therapeutic benefits for Machado-Joseph disease through the induction of autophagy