{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T15:30:43Z","timestamp":1786116643439,"version":"build-2736575974"},"posted":{"date-parts":[[2026,7,30]]},"group-title":"Neuroscience","reference-count":39,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T00:00:00Z","timestamp":1785369600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"NIH","award":["R00AG061231"],"award-info":[{"award-number":["R00AG061231"]}]},{"name":"NIH","award":["R01AG093941"],"award-info":[{"award-number":["R01AG093941"]}]},{"name":"The University of Texas at Dallas Rockford Draper Early Career Development Award"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,8,4]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  In the brain, the water channel Aquaporin 4 (AQP4) is largely restricted to astrocytes, enriched at perivascular astrocytic processes, and involved in fluid balance and neurological disease. The perivascular pool is functionally unique as it is depolarized in diseases, targeted by neuromyelitis optica autoantibodies, and implicated in the clearance of brain metabolites such as amyloid beta. The perivascular AQP4 was recently shown to be AQP4X, an extended isoform arising from readthrough, where approximately 20% of translating ribosomes continue through the\n                  <jats:italic>Aqp4<\/jats:italic>\n                  stop codon. Because\n                  <jats:italic>Aqp4<\/jats:italic>\n                  terminates with a UGA, here we tested whether\n                  <jats:italic>Aqp4<\/jats:italic>\n                  readthrough can be enhanced by 2,6-diaminopurine, a purine analog known to promote UGA decoding. Using dual luciferase and immunoblotting for AQP4X in cultured cells, we show that the drug promotes\n                  <jats:italic>Aqp4<\/jats:italic>\n                  readthrough and increases AQP4X levels. For\n                  <jats:italic>in vivo<\/jats:italic>\n                  validation, we use the wild-type mouse as well as a genetically engineered mouse with a stop-to-sense mutation allowing\n                  <jats:italic>Aqp4<\/jats:italic>\n                  readthrough at 100%. 2,6-diaminopurine elevates perivascular AQP4X levels by approximately 10% after 20 hours of single intracranial injection. It fails to enhance AQP4X levels in animals with stop-to-sense mutation, suggesting its action involves\n                  <jats:italic>Aqp4<\/jats:italic>\n                  readthrough.\n                  <jats:italic>Aqp4<\/jats:italic>\n                  readthrough can be a pharmacological target for modulating perivascular AQP4X in neurological disease models.\n                <\/jats:p>","DOI":"10.64898\/2026.07.27.741080","type":"posted-content","created":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T17:30:15Z","timestamp":1785432615000},"source":"Crossref","is-referenced-by-count":0,"title":["2,6-diaminopurine enhances Aqp4 stop codon readthrough and\n                  <i>AQP4<\/i>\n                  perivascular localization in the brain"],"prefix":"10.64898","author":[{"given":"Sadan","family":"Dahal","sequence":"first","affiliation":[{"name":"Department of Biological Sciences, University of Texas at Dallas, Richardson, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ezzeldin N","family":"Elhawary","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, University of Texas at Dallas, Richardson, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Prarthana","family":"Suresh","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, University of Texas at Dallas, Richardson, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhan","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, University of Texas at Dallas, Richardson, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hamza","family":"Lalami","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, University of Texas at Dallas, Richardson, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alyssa M","family":"Le","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, University of Texas at Dallas, Richardson, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3773-2910","authenticated-orcid":false,"given":"Darshan","family":"Sapkota","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, University of Texas at Dallas, Richardson, TX, USA"},{"name":"Department of Neuroscience, University of Texas at Dallas, Richardson, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026080604202435000_2026.07.27.741080v2.1","doi-asserted-by":"publisher","DOI":"10.1038\/npp.2012.34"},{"key":"2026080604202435000_2026.07.27.741080v2.2","doi-asserted-by":"crossref","first-page":"8124","DOI":"10.1007\/s12035-019-01661-2","article-title":"Aquaporin 4 Suppresses Neural Hyperactivity and Synaptic Fatigue and Fine-Tunes Neurotransmission to Regulate Visual Function in the Mouse Retina","volume":"56","year":"2019","journal-title":"Mol. 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