{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T23:36:20Z","timestamp":1768520180002,"version":"3.49.0"},"posted":{"date-parts":[[2025,2,11]]},"group-title":"Neuroscience","reference-count":106,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,2,11]],"date-time":"2025-02-11T00:00:00Z","timestamp":1739232000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,2,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Spinocerebellar Ataxia Type 14 (SCA14) is an autosomal dominant neurodegenerative disease caused by mutations in the gene encoding protein kinase C gamma (PKC\u03b3), a Ca\n                  <jats:sup>2+<\/jats:sup>\n                  \/diacylglycerol (DG)-dependent serine\/threonine kinase dominantly expressed in cerebellar Purkinje cells. These mutations impair autoinhibitory constraints to increase the basal activity of the kinase, resulting in deficits in the cerebellum that are not observed upon simple deletion of the gene, and severe ataxia. To better understand the phenotypic impact of aberrant PKC\u03b3 signaling in disease pathology, we developed a knock-in murine model of the SCA14 mutation \u0394F48 in PKC\u03b3. This fully penetrant mutation is severe in humans and is mechanistically informative as it has high basal activity but is unresponsive to agonist stimulation. Genetic, behavioral, and molecular testing revealed that \u0394F48 PKC\u03b3 SCA14 mice have ataxia related phenotypes and an altered cerebellar phosphoproteome, effects that are more severe in male mice. Analysis of existing human data reveal that SCA14 has a significantly earlier age of onset for males compared with females. Our data from this clinically relevant mutation suggest that enhanced basal activity of PKC\u03b3 is necessary and sufficient to cause ataxia and that treatment strategies to modulate aberrant PKC\u03b3 may be particularly beneficial in males.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Summary<\/jats:title>\n                  <jats:p>New mouse model of Spinocerebellar Ataxia Type 14 containing a clinically relevant mutation in PKC\u03b3 identified underlying drivers of the disease and neuroprotection in females.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.02.10.637267","type":"posted-content","created":{"date-parts":[[2025,2,11]],"date-time":"2025-02-11T04:35:18Z","timestamp":1739248518000},"source":"Crossref","is-referenced-by-count":0,"title":["Sex specific disruptions in Protein Kinase C\u03b3 signaling in a mouse model of Spinocerebellar Ataxia Type 14"],"prefix":"10.64898","author":[{"given":"Sarah 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