{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T09:18:50Z","timestamp":1790759930980,"version":"4.1.0"},"reference-count":82,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"753","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Sci. Signal."],"published-print":{"date-parts":[[2022,9,27]]},"abstract":"<jats:p>\n            Spinocerebellar ataxia type 14 (SCA14) is a neurodegenerative disease caused by germline variants in the diacylglycerol (DAG)\/Ca\n            <jats:sup>2+<\/jats:sup>\n            -regulated protein kinase C\u03b3 (PKC\u03b3), leading to Purkinje cell degeneration and progressive cerebellar dysfunction. Most of the identified mutations cluster in the DAG-sensing C1 domains. Here, we found with a FRET-based activity reporter that SCA14-associated PKC\u03b3 mutations, including a previously undescribed variant, D115Y, enhanced the basal activity of the kinase by compromising its autoinhibition. Unlike other mutations in PKC that impair its autoinhibition but lead to its degradation, the C1 domain mutations protected PKC\u03b3 from such down-regulation. This enhanced basal signaling rewired the brain phosphoproteome, as revealed by phosphoproteomic analysis of cerebella from mice expressing a human SCA14-associated H101Y mutant PKC\u03b3 transgene. Mutations that induced a high basal activity in vitro were associated with earlier average age of onset in patients. Furthermore, the extent of disrupted autoinhibition, but not agonist-stimulated activity, correlated with disease severity. Molecular modeling indicated that almost all SCA14 variants not within the C1 domain were located at interfaces with the C1B domain, suggesting that mutations in and proximal to the C1B domain are a susceptibility for SCA14 because they uniquely enhance PKC\u03b3 basal activity while protecting the enzyme from down-regulation. These results provide insight into how PKC\u03b3 activation is modulated and how deregulation of the cerebellar phosphoproteome by SCA14-associated mutations affects disease progression.\n          <\/jats:p>","DOI":"10.1126\/scisignal.abk1147","type":"journal-article","created":{"date-parts":[[2022,9,27]],"date-time":"2022-09-27T17:58:11Z","timestamp":1664301491000},"source":"Crossref","is-referenced-by-count":22,"title":["Mutations in protein kinase C\u03b3 promote spinocerebellar ataxia type 14 by impairing kinase autoinhibition"],"prefix":"10.1126","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5730-9995","authenticated-orcid":true,"given":"Caila A.","family":"Pilo","sequence":"first","affiliation":[{"name":"Department of Pharmacology, University of California, San Diego, La Jolla, CA 92037, USA."},{"name":"Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla, CA 92037, 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