{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,3,13]],"date-time":"2026-03-13T03:09:36Z","timestamp":1773371376892,"version":"3.50.1"},"posted":{"date-parts":[[2026,3,10]]},"group-title":"Neuroscience","reference-count":56,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T00:00:00Z","timestamp":1773100800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R35 NS127327"],"award-info":[{"award-number":["R35 NS127327"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["ZIA MH002987"],"award-info":[{"award-number":["ZIA MH002987"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,3,10]]},"abstract":"<jats:title>SUMMARY<\/jats:title>\n                <jats:p>\n                  Although it has been known for over 30 years that CAG trinucleotide repeat expansions in the\n                  <jats:italic>HTT<\/jats:italic>\n                  gene are the cause of Huntington\u2019s disease (HD), it is still not understood how these mutations lead to the loss of striatal spiny projection neurons (SPNs) and other vulnerable neuronal cell types in HD. Here we show that\n                  <jats:italic>SCN4B<\/jats:italic>\n                  , a gene that is enriched in neurons that influence motor function, including striatal SPNs, modulates HD-associated phenotypes\n                  <jats:italic>in vivo<\/jats:italic>\n                  . Loss of\n                  <jats:italic>Scn4b<\/jats:italic>\n                  in wild-type mice mimics and\n                  <jats:italic>Scn4b<\/jats:italic>\n                  overexpression in an HD mouse model rescues several HD-associated phenotypes, including motor and cognitive deficits. Single nucleus RNA sequencing (snRNA-seq) analysis reveals that loss of\n                  <jats:italic>Scn4b<\/jats:italic>\n                  replicates several HD-associated gene expression signatures in the striatum. Conversely, overexpression of\n                  <jats:italic>Scn4b<\/jats:italic>\n                  rescues HD gene expression signatures and improves various SPN electrophysiological properties in HD model mice. Taken together, our results implicate loss of\n                  <jats:italic>Scn4b<\/jats:italic>\n                  expression as an important contributor to HD pathogenesis and therapeutic target in HD.\n                <\/jats:p>","DOI":"10.64898\/2026.03.08.708251","type":"posted-content","created":{"date-parts":[[2026,3,11]],"date-time":"2026-03-11T03:30:13Z","timestamp":1773199813000},"source":"Crossref","is-referenced-by-count":0,"title":["Scn4b Modulates Huntington\u2019s Disease Phenotype Severity in vivo"],"prefix":"10.64898","author":[{"given":"Suphinya","family":"Sathitloetsakun","sequence":"first","affiliation":[{"name":"The Picower Institute for Learning and Memory, MIT, Cambridge, MA 02139, USA"},{"name":"Department of Biology, MIT, Cambridge, MA 02139, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vanessa","family":"Farrell","sequence":"additional","affiliation":[{"name":"The Picower Institute for Learning and Memory, MIT, Cambridge, MA 02139, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8903-0550","authenticated-orcid":false,"given":"S. Sebastian","family":"Pineda","sequence":"additional","affiliation":[{"name":"The Picower Institute for Learning and Memory, MIT, Cambridge, MA 02139, USA"},{"name":"Computer Science and Artificial Intelligence Lab, MIT, Cambridge, MA 02139, USA"},{"name":"The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA"},{"name":"Illumina Artificial Intelligence Laboratory, Illumina Inc., San Diego, CA 92122, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hyeseung","family":"Lee","sequence":"additional","affiliation":[{"name":"The Picower Institute for Learning and Memory, MIT, Cambridge, MA 02139, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jung Hoon","family":"Shin","sequence":"additional","affiliation":[{"name":"Laboratory on Neurobiology of Compulsive Behaviors, NIMH, NIAAA, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francisco J.","family":"Garcia","sequence":"additional","affiliation":[{"name":"The Picower Institute for Learning and Memory, MIT, Cambridge, MA 02139, USA"},{"name":"Department of Brain and Cognitive Sciences, MIT, Cambridge, MA 02139, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Raleigh M.","family":"Linville","sequence":"additional","affiliation":[{"name":"The Picower Institute for Learning and Memory, MIT, Cambridge, MA 02139, USA"},{"name":"The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7113-9630","authenticated-orcid":false,"given":"Manolis","family":"Kellis","sequence":"additional","affiliation":[{"name":"Computer Science and Artificial Intelligence Lab, MIT, Cambridge, MA 02139, USA"},{"name":"The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Veronica 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