{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T17:15:08Z","timestamp":1787505308312,"version":"build-2736575974"},"reference-count":35,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T00:00:00Z","timestamp":1779148800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T00:00:00Z","timestamp":1779148800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Ann Clin Transl Neurol"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>\n                      Variants in\n                      <jats:italic>SLC6A1<\/jats:italic>\n                      , encoding the GABA transporter 1 (GAT\u20101), cause epilepsy, autism spectrum disorder, and developmental delay via loss of GABA uptake, impaired trafficking, and ER retention. We previously found that 4\u2010Phenylbutyrate (PBA), an FDA\u2010approved drug, restores GABA uptake and reduces seizures in\n                      <jats:italic>SLC6A1<\/jats:italic>\n                      \u2010related disorders, prompting a phase I clinical trial (NCT04937062) primarily designed to evaluate safety and tolerability of Ravicti (PBA). However, its exact mechanism, pharmacochaperoning or histone deacetylase (HDAC) inhibition, remains unclear. This study compares PBA with pharmacochaperones and HDAC inhibitors to determine how it restores GAT\u20101 function in the cell and mouse models.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We evaluated the function for 32\n                      <jats:italic>SLC6A1<\/jats:italic>\n                      variants and two representative mouse models at baseline and various treatment options using\n                      <jats:sup>3<\/jats:sup>\n                      H GABA uptake assays. We evaluated the effect of PBA in comparison with other chaperone inducers or HDAC inhibitors on the mutant and the wild\u2010type GAT\u20101 expression. Importantly, we evaluated the effect of chaperone inducers and HDAC inhibitors on GAT\u20101 function and seizures in two representative knock\u2010in mouse models,\n                      <jats:italic>Slc6a1<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>+\/A288V<\/jats:italic>\n                      <\/jats:sup>\n                      and\n                      <jats:italic>Slc6a1<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>+\/S295L<\/jats:italic>\n                      <\/jats:sup>\n                      , with EEG recordings.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>PBA restored GABA uptake and GAT\u20101 surface expression across all variants, and TUDCA mimicked the effects of PBA. HDAC inhibitors exhibited modest rescue in\u00a0vitro but failed to restore GAT\u20101 function or mitigate seizures in the knockin mice.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Interpretation<\/jats:title>\n                    <jats:p>\n                      PBA acts as a pharmacochaperone, not an HDAC inhibitor, to restore GAT\u20101 function and reduce seizure burden in the diseased mice, supporting pharmacochaperoning as the major mechanism for rescuing\n                      <jats:italic>SLC6A1<\/jats:italic>\n                      \u2010related disorders.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/acn3.70430","type":"journal-article","created":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T04:51:38Z","timestamp":1779252698000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Unraveling 4\u2010Phenylbutyrate's Therapeutic Role in\n                    <scp>SLC6A1<\/scp>\n                    Disorders: Pharmacochaperoning Over\n                    <scp>HDAC<\/scp>\n                    Inhibition"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7700-016X","authenticated-orcid":false,"given":"Melissa B.","family":"DeLeeuw","sequence":"first","affiliation":[{"name":"Department of Neurology Vanderbilt University Medical Center  Nashville Tennessee USA"},{"name":"Neuroscience Graduate Program TMNH  Nashville Tennessee USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karishma","family":"Randhave","sequence":"additional","affiliation":[{"name":"Department of Neurology Vanderbilt University Medical Center  Nashville Tennessee USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ekta","family":"Anand","sequence":"additional","affiliation":[{"name":"Vanderbilt Brain Institute TMNH  Nashville Tennessee USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziang","family":"(Debbie) Song","sequence":"additional","affiliation":[{"name":"Department of Neurology Vanderbilt University Medical Center  Nashville Tennessee USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wangzhen","family":"Shen","sequence":"additional","affiliation":[{"name":"Department of Neurology Vanderbilt University Medical Center  Nashville Tennessee USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1079-5436","authenticated-orcid":false,"given":"Jing\u2010Qiong","family":"Kang","sequence":"additional","affiliation":[{"name":"Department of Neurology Vanderbilt University Medical Center  Nashville Tennessee USA"},{"name":"Neuroscience Graduate Program TMNH  Nashville Tennessee USA"},{"name":"Vanderbilt Brain Institute TMNH  Nashville Tennessee USA"},{"name":"Vanderbilt University  Nashville Tennessee USA"},{"name":"Department of Pharmacology Vanderbilt University Medical Center  Nashville Tennessee USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,5,19]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1093\/braincomms\/fcaa170"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awab207"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1124\/pr.108.000869"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2021.113723"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13041-020-00612-6"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00424\u2010014\u20101555\u20106"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.prostaglandins.2024.106836"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.1111\/epi.17342"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2019.112973"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms25094601"},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/nn.4024"},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.1093\/braincomms\/fcae110"},{"key":"e_1_2_12_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.23947"},{"key":"e_1_2_12_15_1","doi-asserted-by":"publisher","DOI":"10.1093\/jb\/mvad095"},{"key":"e_1_2_12_16_1","doi-asserted-by":"publisher","DOI":"10.1093\/braincomms\/fcac144"},{"key":"e_1_2_12_17_1","article-title":"4\u2010Phenylbutyrate for STXBP1 and SLC6A1. 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