{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T18:32:19Z","timestamp":1790620339656,"version":"4.1.0"},"reference-count":97,"publisher":"American Society for Clinical Investigation","issue":"13","license":[{"start":{"date-parts":[[2022,7,8]],"date-time":"2022-07-08T00:00:00Z","timestamp":1657238400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R01NS109640"],"award-info":[{"award-number":["R01NS109640"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"name":"University of Pennsylvania Orphan Disease Center","award":["MDBR-2018-128"],"award-info":[{"award-number":["MDBR-2018-128"]}]},{"name":"University of Pennsylvania Orphan Disease Center","award":["MDBR-20-135-SRS"],"award-info":[{"award-number":["MDBR-20-135-SRS"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,7,8]]},"abstract":"<jats:p>\n                    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\n                    <jats:italic>Drosophila<\/jats:italic>\n                    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\n                    <jats:italic>Drosophila<\/jats:italic>\n                    model and patient fibroblast cell models. PBA treatment significantly restored the function of mitochondria and autolysosomes and extended life span in vivo in the\n                    <jats:italic>Drosophila<\/jats:italic>\n                    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 N\n                    <jats:sup>1<\/jats:sup>\n                    -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\u2013related diseases.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.158457","type":"journal-article","created":{"date-parts":[[2022,7,7]],"date-time":"2022-07-07T14:00:56Z","timestamp":1657202456000},"source":"Crossref","is-referenced-by-count":18,"title":["Phenylbutyrate modulates polyamine acetylase and ameliorates Snyder-Robinson syndrome in a Drosophila model and patient cells"],"prefix":"10.1172","volume":"7","author":[{"given":"Xianzun","family":"Tao","sequence":"first","affiliation":[{"name":"Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, Florida, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1778-8880","authenticated-orcid":true,"given":"Yi","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, Florida, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zoraida","family":"Diaz-Perez","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, Florida, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8372-1094","authenticated-orcid":true,"given":"Seok-Ho","family":"Yu","sequence":"additional","affiliation":[{"name":"JC Self Research Institute, Greenwood Genetic Center, Greenwood, South Carolina, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jackson R.","family":"Foley","sequence":"additional","affiliation":[{"name":"Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, Maryland, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tracy Murray","family":"Stewart","sequence":"additional","affiliation":[{"name":"Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, Maryland, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"Jr.","given":"Robert A.","family":"Casero","sequence":"additional","affiliation":[{"name":"Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, Maryland, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0975-4963","authenticated-orcid":true,"given":"Richard","family":"Steet","sequence":"additional","affiliation":[{"name":"JC Self Research Institute, Greenwood Genetic Center, Greenwood, South Carolina, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0956-9784","authenticated-orcid":true,"given":"R. 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