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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 \u03b2 production in the hippocampus and cortex. CIC, however, forms a complex with ATXN1 and its paralog, Ataxin-1-like (ATXN1L), yet 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 early postnatal 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\/gad.353596.125","type":"journal-article","created":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T17:15:18Z","timestamp":1784567718000},"page":"1267-1282","source":"Crossref","is-referenced-by-count":1,"title":["Functional divergence of Capicua isoforms explains differential tissue vulnerability in neurological disease"],"prefix":"10.1101","volume":"40","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, Texas 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's Hospital, Houston, Texas 77030, 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