{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,3,28]],"date-time":"2026-03-28T17:52:20Z","timestamp":1774720340013,"version":"3.50.1"},"posted":{"date-parts":[[2025,11,5]]},"group-title":"Molecular Biology","reference-count":59,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,11,5]],"date-time":"2025-11-05T00:00:00Z","timestamp":1762300800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"National Institute of Aging","award":["F31 AG077918"],"award-info":[{"award-number":["F31 AG077918"]}]},{"name":"Cockrell Family Funding"},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"crossref","award":["R01 NS027699"],"award-info":[{"award-number":["R01 NS027699"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Freedom Together Foundation grant","award":["MR-2023-4260"],"award-info":[{"award-number":["MR-2023-4260"]}]},{"DOI":"10.13039\/100000011","name":"Howard Hughes Medical Institute","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100000011","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Chao Endowment"},{"DOI":"10.13039\/100017236","name":"Huffington Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100017236","id-type":"DOI","asserted-by":"crossref"}]},{"name":"National Institutes of Health Cancer Center Grant","award":["P30 CA125123"],"award-info":[{"award-number":["P30 CA125123"]}]},{"name":"Cancer Biology Research Grant","award":["1R50CA283804"],"award-info":[{"award-number":["1R50CA283804"]}]},{"name":"Eunice Kennedy Shriver National Institute of Child Health and Human Development Intellectual and Developmental Disabilities Research Center","award":["P50HD103555"],"award-info":[{"award-number":["P50HD103555"]}]},{"DOI":"10.13039\/100000050","name":"National Heart Lung and Blood Institute","doi-asserted-by":"crossref","award":["R01HL181470"],"award-info":[{"award-number":["R01HL181470"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,3,26]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>Many neurological diseases impact specific brain regions despite widespread expression of the disease-related protein. Spinocerebellar ataxia type 1 (SCA1) primarily affects the cerebellum, though Ataxin-1 (ATXN1) is widely expressed. We previously showed that intensified interaction between mutant ATXN1 and Capicua (CIC) drives SCA1 pathogenesis in the cerebellum, whereas ATXN1 loss augments amyloid beta production in the hippocampus and cortex. CIC, however, forms a complex with ATXN1 and its paralog, Ataxin-1-like (ATXN1L)\u2014yet knockout of either yields completely different phenotypes. To determine whether this could be due to CIC having two isoforms, we generated mice bearing either the long (CIC-L) or short (CIC-S) isoform. Loss of CIC-L led to cognitive deficits, whereas loss of CIC-S caused perinatal lethality, phenocopying, ATXN1 and ATXN1L knockout mice, respectively. Furthermore, CIC-L preferentially interacts with ATXN1, and CIC-S with ATXN1L. Our data underscore the importance of isoform\u2013paralog interplay in studying regional vulnerability in neurodegenerative diseases.<\/jats:p>","DOI":"10.1101\/2025.11.05.686788","type":"posted-content","created":{"date-parts":[[2025,11,6]],"date-time":"2025-11-06T04:05:14Z","timestamp":1762401914000},"source":"Crossref","is-referenced-by-count":0,"title":["Functional divergence of Capicua isoforms explains differential tissue vulnerability in neurological disease"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6690-5342","authenticated-orcid":false,"given":"Hamin","family":"Lee","sequence":"first","affiliation":[{"name":"Program in Genetics and Genomics, Baylor College of Medicine, Houston, TX 77030, USA"},{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA"},{"name":"Jan and Dan Duncan Neurological Research Institute at Texas Children\u2019s Hospital, Houston, Texas 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8153-8432","authenticated-orcid":false,"given":"Esmeralda Villavicencio","family":"Gonzalez","sequence":"additional","affiliation":[{"name":"Program in Genetics and Genomics, Baylor College of Medicine, Houston, TX 77030, USA"},{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA"},{"name":"Jan and Dan Duncan Neurological Research Institute at Texas Children\u2019s Hospital, Houston, Texas 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5547-6733","authenticated-orcid":false,"given":"Elias M.","family":"Rivera","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA"},{"name":"Jan and Dan Duncan Neurological Research Institute at Texas Children\u2019s Hospital, Houston, Texas 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark A.","family":"Durham","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA"},{"name":"Jan and Dan Duncan Neurological Research Institute at Texas Children\u2019s Hospital, Houston, Texas 77030, USA"},{"name":"Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA"},{"name":"Medical Scientist Training Program, Baylor College of Medicine, Houston, TX 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ronald","family":"Richman","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA"},{"name":"Jan and Dan Duncan Neurological Research Institute at Texas Children\u2019s Hospital, Houston, Texas 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6277-0962","authenticated-orcid":false,"given":"Elizabeth H.-Y.","family":"Chu","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA"},{"name":"Jan and Dan Duncan Neurological Research Institute at Texas Children\u2019s Hospital, Houston, Texas 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kailey","family":"Xia","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA"},{"name":"Jan and Dan Duncan Neurological Research Institute at Texas Children\u2019s Hospital, Houston, Texas 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hu","family":"Chen","sequence":"additional","affiliation":[{"name":"Jan and Dan Duncan Neurological Research Institute at Texas Children\u2019s Hospital, Houston, Texas 77030, USA"},{"name":"Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7608-0831","authenticated-orcid":false,"given":"Zhandong","family":"Liu","sequence":"additional","affiliation":[{"name":"Jan and Dan Duncan Neurological Research Institute at Texas Children\u2019s Hospital, Houston, Texas 77030, USA"},{"name":"Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7921-7944","authenticated-orcid":false,"given":"Surabi","family":"Veeraragavan","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA"},{"name":"Jan and Dan Duncan Neurological Research Institute at Texas Children\u2019s Hospital, Houston, Texas 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8119-5783","authenticated-orcid":false,"given":"Binoy","family":"Shivanna","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Texas Children\u2019s Hospital, Baylor College of Medicine, Houston, TX 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0700-3349","authenticated-orcid":false,"given":"Huda Y.","family":"Zoghbi","sequence":"additional","affiliation":[{"name":"Program in Genetics and Genomics, Baylor College of Medicine, Houston, TX 77030, USA"},{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA"},{"name":"Jan and Dan Duncan Neurological Research Institute at Texas Children\u2019s Hospital, Houston, Texas 77030, USA"},{"name":"Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA"},{"name":"Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2026032810250906000_2025.11.05.686788v2.1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-09949-6"},{"key":"2026032810250906000_2025.11.05.686788v2.2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddz265"},{"key":"2026032810250906000_2025.11.05.686788v2.3","doi-asserted-by":"publisher","DOI":"10.1038\/ng0894-513"},{"key":"2026032810250906000_2025.11.05.686788v2.4","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2008.10.008"},{"key":"2026032810250906000_2025.11.05.686788v2.5","doi-asserted-by":"crossref","first-page":"1169","DOI":"10.3233\/JAD-2010-1310","article-title":"Follow-up study of susceptibility loci for Alzheimer\u2019s disease and onset age identified by genome-wide association","volume":"19","year":"2010","journal-title":"J Alzheimers Dis"},{"key":"2026032810250906000_2025.11.05.686788v2.6","doi-asserted-by":"publisher","DOI":"10.1038\/ng1977"},{"key":"2026032810250906000_2025.11.05.686788v2.7","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(03)00349-0"},{"key":"2026032810250906000_2025.11.05.686788v2.8","doi-asserted-by":"publisher","DOI":"10.1186\/s13024-021-00476-x"},{"key":"2026032810250906000_2025.11.05.686788v2.9","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2022.11.016"},{"key":"2026032810250906000_2025.11.05.686788v2.10","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1001021"},{"key":"2026032810250906000_2025.11.05.686788v2.11","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20101562"},{"key":"2026032810250906000_2025.11.05.686788v2.12","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1004902"},{"key":"2026032810250906000_2025.11.05.686788v2.13","doi-asserted-by":"crossref","unstructured":"Friedrich J , Kordasiewicz HB , O\u2019Callaghan B , Handler HP , Wagener C , Duvick L , Swayze EE , Rainwater O , Hofstra B , Benneyworth M et al. 2018. Antisense oligonucleotide-mediated ataxin-1 reduction prolongs survival in SCA1 mice and reveals disease-associated transcriptome profiles. JCI Insight 3.","DOI":"10.1172\/jci.insight.123193"},{"key":"2026032810250906000_2025.11.05.686788v2.14","doi-asserted-by":"publisher","DOI":"10.1126\/science.1212673"},{"key":"2026032810250906000_2025.11.05.686788v2.15","doi-asserted-by":"crossref","unstructured":"Fu H , Hardy J , Duff KE , Fu H , Hardy J , Duff KE . 2018. Selective vulnerability in neurodegenerative diseases. Nature Neuroscience 2018 21:10 21.","DOI":"10.1038\/s41593-018-0221-2"},{"key":"2026032810250906000_2025.11.05.686788v2.16","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2018.02.006"},{"key":"2026032810250906000_2025.11.05.686788v2.17","doi-asserted-by":"publisher","DOI":"10.1038\/ncb3438"},{"key":"2026032810250906000_2025.11.05.686788v2.18","doi-asserted-by":"crossref","unstructured":"Hwang I , Pan H , Yao J , Elemento O , Zheng H , Paik J . 2020. CIC is a critical regulator of neuronal differentiation. JCI Insight 5.","DOI":"10.1172\/jci.insight.135826"},{"key":"2026032810250906000_2025.11.05.686788v2.19","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1018748108"},{"key":"2026032810250906000_2025.11.05.686788v2.20","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.092965"},{"key":"2026032810250906000_2025.11.05.686788v2.21","doi-asserted-by":"publisher","DOI":"10.1038\/s41583-024-00806-0"},{"key":"2026032810250906000_2025.11.05.686788v2.22","doi-asserted-by":"publisher","DOI":"10.1038\/325733a0"},{"key":"2026032810250906000_2025.11.05.686788v2.23","doi-asserted-by":"publisher","DOI":"10.1101\/gad.212068.112"},{"key":"2026032810250906000_2025.11.05.686788v2.24","doi-asserted-by":"crossref","first-page":"8272","DOI":"10.1038\/srep08272","article-title":"Deficiency of Capicua disrupts bile acid homeostasis","volume":"5","year":"2015","journal-title":"Sci Rep"},{"key":"2026032810250906000_2025.11.05.686788v2.25","doi-asserted-by":"publisher","DOI":"10.1038\/331530a0"},{"key":"2026032810250906000_2025.11.05.686788v2.26","doi-asserted-by":"publisher","DOI":"10.1038\/s41573-024-01025-z"},{"key":"2026032810250906000_2025.11.05.686788v2.27","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-03220-z"},{"key":"2026032810250906000_2025.11.05.686788v2.28","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2006.11.038"},{"key":"2026032810250906000_2025.11.05.686788v2.29","doi-asserted-by":"publisher","DOI":"10.1038\/s12276-020-0411-3"},{"key":"2026032810250906000_2025.11.05.686788v2.30","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2011.08.017"},{"key":"2026032810250906000_2025.11.05.686788v2.31","doi-asserted-by":"publisher","DOI":"10.1038\/nature06731"},{"key":"2026032810250906000_2025.11.05.686788v2.32","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3808"},{"key":"2026032810250906000_2025.11.05.686788v2.33","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.18-14-05508.1998"},{"key":"2026032810250906000_2025.11.05.686788v2.34","doi-asserted-by":"publisher","DOI":"10.1038\/sj.emboj.7600785"},{"key":"2026032810250906000_2025.11.05.686788v2.35","doi-asserted-by":"publisher","DOI":"10.1038\/ng0793-221"},{"key":"2026032810250906000_2025.11.05.686788v2.36","doi-asserted-by":"publisher","DOI":"10.1038\/331525a0"},{"key":"2026032810250906000_2025.11.05.686788v2.37","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms2032"},{"key":"2026032810250906000_2025.11.05.686788v2.38","doi-asserted-by":"crossref","first-page":"e2123467119","DOI":"10.1073\/pnas.2123467119","article-title":"Noncanonical function of Capicua as a growth termination signal in Drosophila oogenesis","volume":"119","year":"2022","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2026032810250906000_2025.11.05.686788v2.39","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2018.02.013"},{"key":"2026032810250906000_2025.11.05.686788v2.40","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2006.09.036"},{"key":"2026032810250906000_2025.11.05.686788v2.41","doi-asserted-by":"publisher","DOI":"10.1038\/ng0595-94"},{"key":"2026032810250906000_2025.11.05.686788v2.42","doi-asserted-by":"publisher","DOI":"10.1002\/humu.24346"},{"key":"2026032810250906000_2025.11.05.686788v2.43","doi-asserted-by":"crossref","first-page":"L229","DOI":"10.1152\/ajplung.00560.2017","article-title":"Consequences of early postnatal lipopolysaccharide exposure on developing lungs in mice","volume":"316","year":"2019","journal-title":"Am J Physiol Lung Cell Mol Physiol"},{"key":"2026032810250906000_2025.11.05.686788v2.44","doi-asserted-by":"publisher","DOI":"10.1101\/gad.300244.117"},{"key":"2026032810250906000_2025.11.05.686788v2.45","doi-asserted-by":"publisher","DOI":"10.1021\/bi00068a002"},{"key":"2026032810250906000_2025.11.05.686788v2.46","doi-asserted-by":"crossref","unstructured":"Subramanian A , Tamayo P , Mootha VK , Mukherjee S , Ebert BL , Gillette MA , Paulovich A , Pomeroy SL , Golub TR , Lander ES et al. 2005. Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles. Proceedings of the National Academy of Sciences 102.","DOI":"10.1073\/pnas.0506580102"},{"key":"2026032810250906000_2025.11.05.686788v2.47","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2019.07.043"},{"key":"2026032810250906000_2025.11.05.686788v2.48","doi-asserted-by":"crossref","first-page":"729478","DOI":"10.4061\/2011\/729478","article-title":"Genomic Copy Number Analysis in Alzheimer\u2019s Disease and Mild Cognitive Impairment: An ADNI Study","volume":"2011","year":"2011","journal-title":"Int J Alzheimers Dis"},{"key":"2026032810250906000_2025.11.05.686788v2.49","doi-asserted-by":"publisher","DOI":"10.2174\/156720512802455331"},{"key":"2026032810250906000_2025.11.05.686788v2.50","doi-asserted-by":"publisher","DOI":"10.1016\/j.nlm.2018.07.006"},{"key":"2026032810250906000_2025.11.05.686788v2.51","doi-asserted-by":"publisher","DOI":"10.1038\/331528a0"},{"key":"2026032810250906000_2025.11.05.686788v2.52","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2005.06.012"},{"key":"2026032810250906000_2025.11.05.686788v2.53","doi-asserted-by":"publisher","DOI":"10.1038\/nrn.2015.1"},{"key":"2026032810250906000_2025.11.05.686788v2.54","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.89.22.10758"},{"key":"2026032810250906000_2025.11.05.686788v2.55","doi-asserted-by":"publisher","DOI":"10.1038\/ng0993-95"},{"key":"2026032810250906000_2025.11.05.686788v2.56","doi-asserted-by":"publisher","DOI":"10.1158\/1538-7445.AM2018-4114"},{"key":"2026032810250906000_2025.11.05.686788v2.57","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1186\/s12915-020-00895-0","article-title":"TRIM25 promotes Capicua degradation independently of ERK in the absence of ATXN1L","volume":"18","year":"2020","journal-title":"BMC Biol"},{"key":"2026032810250906000_2025.11.05.686788v2.58","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2016.01.029"},{"key":"2026032810250906000_2025.11.05.686788v2.59","doi-asserted-by":"publisher","DOI":"10.1016\/1043-4682(95)90012-8"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2025.11.05.686788","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,28]],"date-time":"2026-03-28T17:25:18Z","timestamp":1774718718000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2025.11.05.686788"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,5]]},"references-count":59,"URL":"https:\/\/doi.org\/10.1101\/2025.11.05.686788","relation":{},"subject":[],"published":{"date-parts":[[2025,11,5]]},"subtype":"preprint"}}