{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T06:47:42Z","timestamp":1776235662826,"version":"3.50.1"},"reference-count":60,"publisher":"Oxford University Press (OUP)","issue":"23","license":[{"start":{"date-parts":[[2024,9,26]],"date-time":"2024-09-26T00:00:00Z","timestamp":1727308800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["R01NS112203"],"award-info":[{"award-number":["R01NS112203"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,11,20]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>LRRK2 mutations are among the most common genetic causes for Parkinson\u2019s disease (PD), and toxicity is associated with increased kinase activity. 14-3-3 proteins are key interactors that regulate LRRK2 kinase activity. Phosphorylation of the 14-3-3\u03b8 isoform at S232 is dramatically increased in human PD brains. Here we investigate the impact of 14-3-3\u03b8 phosphorylation on its ability to regulate LRRK2 kinase activity. Both wildtype and the non-phosphorylatable S232A 14-3-3\u03b8 mutant reduced the kinase activity of wildtype and G2019S LRRK2, whereas the phosphomimetic S232D 14-3-3\u03b8 mutant had minimal effects on LRRK2 kinase activity, as determined by measuring autophosphorylation at S1292 and T1503 and Rab10 phosphorylation. However, wildtype and both 14-3-3\u03b8 mutants similarly reduced the kinase activity of the R1441G LRRK2 mutant. 14-3-3\u03b8 phosphorylation did not promote global dissociation with LRRK2, as determined by co-immunoprecipitation and proximal ligation assays. 14-3-3s interact with LRRK2 at several phosphorylated serine\/threonine sites, including T2524 in the C-terminal helix, which can fold back to regulate the kinase domain. Interaction between 14-3-3\u03b8 and phosphorylated T2524 LRRK2 was important for 14-3-3\u03b8\u2019s ability to regulate kinase activity, as wildtype and S232A 14-3-3\u03b8 failed to reduce the kinase activity of G2019S\/T2524A LRRK2. Finally, we found that the S232D mutation failed to protect against G2019S LRRK2-induced neurite shortening in primary cultures, while the S232A mutation was protective. We conclude that 14-3-3\u03b8 phosphorylation destabilizes the interaction of 14-3-3\u03b8 with LRRK2 at T2524, which consequently promotes LRRK2 kinase activity and toxicity.<\/jats:p>","DOI":"10.1093\/hmg\/ddae142","type":"journal-article","created":{"date-parts":[[2024,9,26]],"date-time":"2024-09-26T08:38:14Z","timestamp":1727339894000},"page":"2071-2083","source":"Crossref","is-referenced-by-count":9,"title":["14-3-3 phosphorylation inhibits 14-3-3\u03b8\u2019s ability to regulate LRRK2 kinase activity and toxicity"],"prefix":"10.1093","volume":"33","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3597-7423","authenticated-orcid":false,"given":"Rudradip","family":"Pattanayak","sequence":"first","affiliation":[{"name":"Center for Neurodegeneration and Experimental Therapeutics , Department of Neurology, Heersink School of Medicine, , 1719 Sixth Avenue South, Civitan International Research Building 510, Birmingham, AL 35294,","place":["United States"]},{"name":"University of Alabama at Birmingham , Department of Neurology, Heersink School of Medicine, , 1719 Sixth Avenue South, Civitan International Research Building 510, Birmingham, AL 35294,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roschongporn","family":"Ekkatine","sequence":"additional","affiliation":[{"name":"Center for Neurodegeneration and Experimental Therapeutics , Department of Neurology, Heersink School of Medicine, , 1719 Sixth Avenue South, Civitan International Research Building 510, Birmingham, AL 35294,","place":["United States"]},{"name":"University of Alabama at Birmingham , Department of Neurology, Heersink School of Medicine, , 1719 Sixth Avenue South, Civitan International Research Building 510, Birmingham, AL 35294,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chad M","family":"Petit","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Genetics , Heersink School of Medicine, , 720 20 th Street South, Kaul 452, Birmingham, AL 35294,","place":["United States"]},{"name":"University of Alabama at Birmingham , Heersink School of Medicine, , 720 20 th Street South, Kaul 452, Birmingham, AL 35294,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2227-7310","authenticated-orcid":false,"given":"Talene A","family":"Yacoubian","sequence":"additional","affiliation":[{"name":"Center for Neurodegeneration and Experimental Therapeutics , Department of Neurology, Heersink School of Medicine, , 1719 Sixth Avenue South, Civitan International Research Building 510, Birmingham, AL 35294,","place":["United States"]},{"name":"University of Alabama at Birmingham , Department of Neurology, Heersink School of Medicine, , 1719 Sixth Avenue South, Civitan International Research Building 510, Birmingham, AL 35294,","place":["United 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