{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T11:59:01Z","timestamp":1779364741771,"version":"3.53.0"},"posted":{"date-parts":[[2024,11,1]]},"group-title":"Neuroscience","reference-count":41,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2024,11,1]],"date-time":"2024-11-01T00:00:00Z","timestamp":1730419200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,1,16]]},"abstract":"<jats:p>\n                  Christianson syndrome (CS) is an x-linked recessive neurodevelopmental and neurodegenerative condition characterized by severe intellectual disability, cerebellar degeneration, ataxia, and epilepsy. Mutations to the\n                  <jats:italic>SLC9A6<\/jats:italic>\n                  gene are responsible for CS, and we recently demonstrated that a mutation to the rat\n                  <jats:italic>Slc9a6<\/jats:italic>\n                  gene causes a similar phenotype in the spontaneous shaker rat model, which exhibits cerebellar degeneration with motor dysfunction. In previous work, we used the PhP.eB-L7-Slc9a6-GFP adeno-associated viral (AAV) vector to demonstrate that gene replacement in Purkinje cells reduced the shaker motor and molecular phenotype. Here, we carried out a 20-week longitudinal study evaluating the impact of Purkinje cell-specific gene replacement on ataxia and tremor. Taking advantage of the high homology between human\n                  <jats:italic>SLC9A6<\/jats:italic>\n                  and rat\n                  <jats:italic>Slc9a6<\/jats:italic>\n                  , we tested a more clinically relevant construct, AAV9-CAG-hSLC9A6 AAV vector in the shaker rat. Administration of either of PhP.eB-L7-Slc9a6-GFP or AAV9-CAG-hSLC9A6 AAV vectors led to significant improvement in the molecular and motor phenotypes. The abundance of several disease-relevant cerebellar proteins was significantly correlated to motor performance. Finally, we found evidence that tremor and ataxia phenotypes in may arise from dissociable cerebellar mechanisms in the context of CS. These findings impact future\n                  <jats:italic>SLC9A6<\/jats:italic>\n                  -targeted gene therapy efforts for CS and strongly support gene replacement as a viable therapeutic strategy.\n                <\/jats:p>","DOI":"10.1101\/2024.10.31.621435","type":"posted-content","created":{"date-parts":[[2024,11,2]],"date-time":"2024-11-02T00:25:19Z","timestamp":1730507119000},"source":"Crossref","is-referenced-by-count":3,"title":["Viral vector-mediated\n                  <i>SLC9A6<\/i>\n                  gene replacement reduces cerebellar dysfunction in the\n                  <i>shaker<\/i>\n                  rat model of Christianson syndrome"],"prefix":"10.64898","author":[{"given":"Collin J","family":"Anderson","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karla P","family":"Figueroa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sharan J","family":"Paul","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mandi","family":"Gandelman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Warunee","family":"Dansithong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph A","family":"Katakowski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel R","family":"Scoles","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan M","family":"Pulst","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025012021304710000_2024.10.31.621435v2.1","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.36.10.759"},{"key":"2025012021304710000_2024.10.31.621435v2.2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2008.01.013"},{"key":"2025012021304710000_2024.10.31.621435v2.3","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awr250"},{"key":"2025012021304710000_2024.10.31.621435v2.4","doi-asserted-by":"publisher","DOI":"10.1242\/dmm.022848"},{"key":"2025012021304710000_2024.10.31.621435v2.5","doi-asserted-by":"publisher","DOI":"10.1002\/ana.25464"},{"key":"2025012021304710000_2024.10.31.621435v2.6","first-page":"3642","article-title":"Detecting and quantifying ataxia-related motor impairments in rodents using markerless motion tracking with deep neural networks","volume":"2020","year":"2020","journal-title":"Annu. 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