{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T10:16:27Z","timestamp":1785406587598,"version":"3.56.0"},"posted":{"date-parts":[[2026,5,26]]},"group-title":"Neuroscience","reference-count":47,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,5,26]],"date-time":"2026-05-26T00:00:00Z","timestamp":1779753600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"award":["NS055028"],"award-info":[{"award-number":["NS055028"]}],"id":[{"id":"https:\/\/ror.org\/001d55x84","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,5,26]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Lethal-wasting (lew) is a spontaneous null mutation in the\n                  <jats:italic>Syb1\/Vamp1<\/jats:italic>\n                  gene encoding the vesicular SNARE protein synaptobrevin 1 (SYB1\/VAMP1). Homozygous\n                  <jats:italic>\n                    Syb1\n                    <jats:sup>lew\/lew<\/jats:sup>\n                  <\/jats:italic>\n                  mice exhibit profound impairment in neuromuscular transmission and die around three weeks after birth. Pathogenic variants in human SYB1 are associated with a variety of disorders such as hereditary spastic ataxia and congenital myasthenic syndrome. Although Syb1 expression is highly enriched in neurons, it has also been reported in non-neuronal tissues, raising the possibility that non-neuronal defects contribute to the lethal phenotype. Here, we tested whether neuronal dysfunction is the primary cause of death in\n                  <jats:italic>\n                    Syb1\n                    <jats:sup>lew\/lew<\/jats:sup>\n                  <\/jats:italic>\n                  mice and whether the closely related isoform synaptobrevin 2 (Syb2\/VAMP2) can substitute for Syb1functin\n                  <jats:italic>in vivo<\/jats:italic>\n                  . We show that neuron-specific expression of\n                  <jats:italic>ECFP-Syb2<\/jats:italic>\n                  in\n                  <jats:italic>\n                    Syb1\n                    <jats:sup>lew\/lew<\/jats:sup>\n                  <\/jats:italic>\n                  mice fully rescues lethality in\n                  <jats:italic>\n                    Syb1\n                    <jats:sup>lew\/lew<\/jats:sup>\n                  <\/jats:italic>\n                  mice, restoring normal growth and motor function. Electrophysiological analyses demonstrate complete recovery of neuromuscular synaptic transmission, including spontaneous and evoked release as well as short-term plasticity. These findings establish that neuronal expression of ECFP-Syb2 is sufficient to prevent the lethal phenotype associated with Syb1 deficiency and demonstrate that Syb2 can functionally replace Syb1 at motor nerve terminals\n                  <jats:italic>in vivo<\/jats:italic>\n                  .\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Significance Statement<\/jats:title>\n                  <jats:p>\n                    Neuron-specific expression of Syb2 fully rescues survival, motor function, and neuromuscular transmission in\n                    <jats:italic>\n                      Syb1\n                      <jats:sup>lew\/lew<\/jats:sup>\n                    <\/jats:italic>\n                    mice. These findings establish presynaptic Syb1 dysfunction as the primary cause of the lethal phenotype and demonstrate that Syb2 can fully substitute for Syb1\n                    <jats:italic>in vivo<\/jats:italic>\n                    .\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.05.22.727260","type":"posted-content","created":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T03:05:17Z","timestamp":1779851117000},"source":"Crossref","is-referenced-by-count":0,"title":["Genetic Rescue of a Lethal Wasting Mutation (\n                  <i>\n                    Syb1\n                    <sup>lew\/lew<\/sup>\n                  <\/i>\n                  ) by Neuron-Specific Expression of ECFP-Syb2"],"prefix":"10.64898","author":[{"given":"Yun","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Neuroscience, UT Southwestern Medical Center, Dallas, TX 75390, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiaohong","family":"Ye","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, UT Southwestern Medical Center, Dallas, TX 75390, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6806-3329","authenticated-orcid":false,"given":"Weichun","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, UT Southwestern Medical Center, Dallas, TX 75390, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026052903400656000_2026.05.22.727260v1.1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.273.17.10317"},{"key":"2026052903400656000_2026.05.22.727260v1.2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.20-15-05724.2000"},{"key":"2026052903400656000_2026.05.22.727260v1.3","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2013.08.024"},{"key":"2026052903400656000_2026.05.22.727260v1.4","doi-asserted-by":"publisher","DOI":"10.1002\/j.1460-2075.1989.tb03388.x"},{"key":"2026052903400656000_2026.05.22.727260v1.5","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2012.07.018"},{"key":"2026052903400656000_2026.05.22.727260v1.6","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.1956.sp005503"},{"key":"2026052903400656000_2026.05.22.727260v1.7","doi-asserted-by":"crossref","first-page":"11061","DOI":"10.1016\/S0021-9258(18)60426-0","article-title":"Two vesicle-associated membrane protein genes are differentially expressed in the rat central nervous system","volume":"264","year":"1989","journal-title":"J. Biol. Chem"},{"key":"2026052903400656000_2026.05.22.727260v1.8","doi-asserted-by":"publisher","DOI":"10.1007\/s11910-018-0852-4"},{"key":"2026052903400656000_2026.05.22.727260v1.9","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2010.08.020"},{"key":"2026052903400656000_2026.05.22.727260v1.10","first-page":"249","article-title":"A founder effect in three large Newfoundland families with a novel clinically variable spastic ataxia and supranuclear gaze palsy","volume":"131","year":"2004","journal-title":"Am J Med Genet A"},{"key":"2026052903400656000_2026.05.22.727260v1.11","doi-asserted-by":"publisher","DOI":"10.1038\/sj.embor.7400018"},{"key":"2026052903400656000_2026.05.22.727260v1.12","doi-asserted-by":"publisher","DOI":"10.1046\/j.1460-9568.1998.00050.x"},{"key":"2026052903400656000_2026.05.22.727260v1.13","doi-asserted-by":"publisher","DOI":"10.1042\/bj3170945"},{"key":"2026052903400656000_2026.05.22.727260v1.14","doi-asserted-by":"publisher","DOI":"10.1038\/s41580-023-00668-x"},{"key":"2026052903400656000_2026.05.22.727260v1.15","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.16-01-00137.1996"},{"key":"2026052903400656000_2026.05.22.727260v1.16","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.5288-14.2015"},{"key":"2026052903400656000_2026.05.22.727260v1.17","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1093\/hmg\/ddad183","article-title":"Morphological and functional alterations of neuromuscular synapses in a mouse model of ACTA1 congenital myopathy","volume":"33","year":"2024","journal-title":"Hum. Mol. Genet"},{"key":"2026052903400656000_2026.05.22.727260v1.18","doi-asserted-by":"publisher","DOI":"10.1242\/dev.018119"},{"key":"2026052903400656000_2026.05.22.727260v1.19","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2010.201939"},{"key":"2026052903400656000_2026.05.22.727260v1.20","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0403-19.2019"},{"key":"2026052903400656000_2026.05.22.727260v1.21","doi-asserted-by":"crossref","unstructured":"Liu, Y. , Q. Ye , D.K. Ma , B.A. Rothermel , and W. Lin . 2025. Bltp1 Is Required for Survival and Normal Development and Function of the Neuromuscular Junction in Mice. J Neurosci. 45.","DOI":"10.1523\/JNEUROSCI.0029-25.2025"},{"key":"2026052903400656000_2026.05.22.727260v1.22","doi-asserted-by":"publisher","DOI":"10.1086\/338933"},{"key":"2026052903400656000_2026.05.22.727260v1.23","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.012211"},{"key":"2026052903400656000_2026.05.22.727260v1.24","doi-asserted-by":"publisher","DOI":"10.1016\/S0306-4522(03)00567-0"},{"key":"2026052903400656000_2026.05.22.727260v1.25","doi-asserted-by":"publisher","DOI":"10.1007\/s10048-006-0068-7"},{"key":"2026052903400656000_2026.05.22.727260v1.26","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3519-06.2006"},{"key":"2026052903400656000_2026.05.22.727260v1.27","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2005.12.007"},{"key":"2026052903400656000_2026.05.22.727260v1.28","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1016\/j.ejpn.2021.02.005","article-title":"Recessive VAMP1 mutations associated with severe congenital myasthenic syndromes - A recognizable clinical phenotype","volume":"31","year":"2021","journal-title":"Eur J Paediatr Neurol"},{"key":"2026052903400656000_2026.05.22.727260v1.29","doi-asserted-by":"publisher","DOI":"10.1038\/nn.3067"},{"key":"2026052903400656000_2026.05.22.727260v1.30","doi-asserted-by":"crossref","first-page":"15403","DOI":"10.1016\/S0021-9258(17)40690-9","article-title":"Expression of the synaptic vesicle proteins VAMPs\/synaptobrevins 1 and 2 in non-neural tissues","volume":"269","year":"1994","journal-title":"J. Biol. Chem"},{"key":"2026052903400656000_2026.05.22.727260v1.31","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2011.10.034"},{"key":"2026052903400656000_2026.05.22.727260v1.32","doi-asserted-by":"publisher","DOI":"10.1016\/j.jchemneu.2005.08.002"},{"key":"2026052903400656000_2026.05.22.727260v1.33","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.132.1.167"},{"key":"2026052903400656000_2026.05.22.727260v1.34","doi-asserted-by":"publisher","DOI":"10.1038\/355409a0"},{"key":"2026052903400656000_2026.05.22.727260v1.35","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2011-10.2011"},{"key":"2026052903400656000_2026.05.22.727260v1.36","doi-asserted-by":"crossref","unstructured":"Rudolf, R. , M.M. Khan , and V. Witzemann . 2019. Motor Endplate-Anatomical, Functional, and Molecular Concepts in the Historical Perspective. Cells. 8.","DOI":"10.3390\/cells8050387"},{"key":"2026052903400656000_2026.05.22.727260v1.37","doi-asserted-by":"publisher","DOI":"10.1002\/ana.24905"},{"key":"2026052903400656000_2026.05.22.727260v1.38","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0603511103"},{"key":"2026052903400656000_2026.05.22.727260v1.39","doi-asserted-by":"publisher","DOI":"10.1126\/science.1064335"},{"key":"2026052903400656000_2026.05.22.727260v1.40","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1002\/acn3.387","article-title":"Novel synaptobrevin-1 mutation causes fatal congenital myasthenic syndrome","volume":"4","year":"2017","journal-title":"Ann Clin Transl Neurol"},{"key":"2026052903400656000_2026.05.22.727260v1.41","first-page":"673","article-title":"Differential distribution of vesicle associated membrane protein isoforms in the mouse retina","volume":"9","year":"2003","journal-title":"Mol Vis"},{"key":"2026052903400656000_2026.05.22.727260v1.42","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.neuro.26.041002.131412"},{"key":"2026052903400656000_2026.05.22.727260v1.43","doi-asserted-by":"publisher","DOI":"10.1016\/0896-6273(89)90193-1"},{"key":"2026052903400656000_2026.05.22.727260v1.44","doi-asserted-by":"publisher","DOI":"10.1126\/science.1161748"},{"key":"2026052903400656000_2026.05.22.727260v1.45","doi-asserted-by":"crossref","unstructured":"Takikawa, K. , and H. Nishimune . 2022. Similarity and Diversity of Presynaptic Molecules at Neuromuscular Junctions and Central Synapses. Biomolecules. 12.","DOI":"10.3390\/biom12020179"},{"key":"2026052903400656000_2026.05.22.727260v1.46","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.85.12.4538"},{"key":"2026052903400656000_2026.05.22.727260v1.47","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1055\/s-0044-1782675","article-title":"VAMP1-Related Congenital Myasthenic Syndrome: A Case Report and Literature Review","volume":"55","year":"2024","journal-title":"Neuropediatrics"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.05.22.727260","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T10:40:15Z","timestamp":1780051215000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.64898\/2026.05.22.727260"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,26]]},"references-count":47,"URL":"https:\/\/doi.org\/10.64898\/2026.05.22.727260","relation":{},"subject":[],"published":{"date-parts":[[2026,5,26]]},"subtype":"preprint"}}