ArticleJCI insight2022
Phenylbutyrate modulates polyamine acetylase and ameliorates Snyder-Robinson syndrome in a Drosophila model and patient cells.
Article in JCI insight, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 16 citations in OpenAlex.
- Metabolic alterations in Snyder-Robinson syndrome lymphoblasts are ameliorated by phenylbutyrate treatment.Molecular genetics and metabolism · 2026Article
- Polyamine Metabolism in Brain Health and Disease.Neuropharmacology and therapy · 2026Article
- Repurposing With Purpose: Treatment of Bachmann-Bupp Syndrome With Eflornithine and Implications for Other Polyaminopathies.American journal of medical genetics. Part C, Seminars in medical genetics · 2025Article
- MALAT1 regulates mRNA processing through sequence dependent RNA-RNA and RNA-protein interactions.Nucleic acids research · 2025Article
- Regulation of polyamine interconversion enzymes affects α-Synuclein levels and toxicity in a Drosophila model of Parkinson's Disease.NPJ Parkinson's disease · 2025Article
- Development and characterization of a Drosophila model of Snyder-Robinson syndrome.Methods in enzymology · 2025Article
- Loss of Fic causes progressive neurodegeneration in a Drosophila model of hereditary spastic paraplegia.Biochimica et biophysica acta. Molecular basis of disease · 2024Article
- Structural Insights into the Mechanisms Underlying Polyaminopathies.International journal of molecular sciences · 2024Review
- Impaired polyamine metabolism causes behavioral and neuroanatomical defects in a mouse model of Snyder-Robinson syndrome.Disease models & mechanisms · 2024Article
- Reduction of spermine synthase enhances autophagy to suppress Tau accumulation.Cell death & disease · 2024Article
- Uncovering the roles ofmSphere · 2024Article
- Difluoromethylornithine rebalances aberrant polyamine ratios in Snyder-Robinson syndrome.EMBO molecular medicine · 2023Article
- Two New Cases of Bachmann-Bupp Syndrome Identified through the International Center for Polyamine Disorders.Medical sciences (Basel, Switzerland) · 2023Article
- Article
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Authors and funding
9 authors at 3 institutions in 1 country.
Funding
Abstract
Polyamine dysregulation plays key roles in a broad range of human diseases from cancer to neurodegeneration. Snyder-Robinson syndrome (SRS) is the first known genetic disorder of the polyamine pathway, caused by X-linked recessive loss-of-function mutations in spermine synthase. In the Drosophila SRS model, altered spermidine/spermine balance has been associated with increased generation of ROS and aldehydes, consistent with elevated spermidine catabolism. These toxic byproducts cause mitochondrial and lysosomal dysfunction, which are also observed in cells from SRS patients. No efficient therapy is available. We explored the biochemical mechanism and discovered acetyl-CoA reduction and altered protein acetylation as potentially novel pathomechanisms of SRS. We repurposed the FDA-approved drug phenylbutyrate (PBA) to treat SRS using an in vivo Drosophila model and patient fibroblast cell models. PBA treatment significantly restored the function of mitochondria and autolysosomes and extended life span in vivo in the Drosophila SRS model. Treating fibroblasts of patients with SRS with PBA ameliorated autolysosome dysfunction. We further explored the mechanism of drug action and found that PBA downregulates the first and rate-limiting spermidine catabolic enzyme spermidine/spermine N1-acetyltransferase 1 (SAT1), reduces the production of toxic metabolites, and inhibits the reduction of the substrate acetyl-CoA. Taken together, we revealed PBA as a potential modulator of SAT1 and acetyl-CoA levels and propose PBA as a therapy for SRS and potentially other polyamine dysregulation-related diseases.
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Registered trials
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