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Fox Foundation for Parkinson's Research","doi-asserted-by":"publisher","award":["6709.3"],"award-info":[{"award-number":["6709.3"]}],"id":[{"id":"10.13039\/100000864","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100008383","name":"Stichting ParkinsonFonds","doi-asserted-by":"publisher","award":["1912"],"award-info":[{"award-number":["1912"]}],"id":[{"id":"10.13039\/501100008383","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2026,6,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most frequent cause of late-onset familial and idiopathic Parkinson\u2019s disease (PD), known to date. Importantly, recent data from postmortem tissue as well as biomarker studies suggest that independent of mutations, increased kinase activity of LRRK2 plays an essential role in idiopathic PD pathogenesis. Despite extensive research on LRRK2, its activation mechanism(s) and how the various mutations result in increased kinase activity and neuronal death are still not completely understood. Accumulating evidence points to LRRK2 phosphoregulation, both autophosphorylation and phosphorylation by other kinases, as one potential molecular trigger of its activation. LRRK2 activation and localization are regulated by phosphatases such as protein phosphatase 1 (PP1) and protein phosphatase 2A (PP2A); however, the exact mechanism of this phosphoregulation is not known. Our data reveal that in vitro PP2A dephosphorylates sites within the RocCOR-GTPase domain of LRRK2 and, as a result, destabilizes LRRK2 dimers, with consequent reduction of its kinase activity. Strikingly, our data further highlight that LRRK2 in turn phosphorylates the catalytic subunit of the PP2A holoenzyme PPP2CA at its critical residue T304. Furthermore, LRRK2-mediated phosphorylation of PP2CA T304 alters the methylation of the C-terminus, which is crucial for both holoenzyme formation and catalytic activity. Importantly, expression of WT-PPP2CA protects from LRRK2-G2019S-induced neuronal cell death, while the PPP2CA-T304A mutant fails to do so, suggesting that impaired PP2A holoenzyme formation might be detrimental for LRRK2-PD.<\/jats:p>","DOI":"10.1042\/bcj20260194","type":"journal-article","created":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T15:29:16Z","timestamp":1778772556000},"page":"1097-1114","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Regulation between LRRK2 and PP2A signaling in cellular models of Parkinson\u2019s disease"],"prefix":"10.1042","volume":"483","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2255-9433","authenticated-orcid":false,"given":"Panagiotis\u00a0S.","family":"Athanasopoulos","sequence":"first","affiliation":[{"name":"1Department of Cell Biochemistry, University of Groningen, Nijenborgh 7, 9747 AG Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Memou","sequence":"additional","affiliation":[{"name":"2Center for Clinical, Experimental Surgery, and Translational Research; Biomedical Research Foundation of the Academy of Athens, Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Franz\u00a0Y.","family":"Ho","sequence":"additional","affiliation":[{"name":"1Department of Cell Biochemistry, University of Groningen, Nijenborgh 7, 9747 AG Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmed","family":"Soliman","sequence":"additional","affiliation":[{"name":"1Department of Cell Biochemistry, University of Groningen, Nijenborgh 7, 9747 AG Groningen, The Netherlands"},{"name":"3Division of Engineering in Medicine, Department of Medicine, Brigham Women\u2019s Hospital, Harvard Medical School, Boston, MA 02115, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henderikus","family":"Pots","sequence":"additional","affiliation":[{"name":"1Department of Cell Biochemistry, University of Groningen, Nijenborgh 7, 9747 AG Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vassiliki","family":"Papadopoulou","sequence":"additional","affiliation":[{"name":"2Center for Clinical, Experimental Surgery, and Translational Research; Biomedical Research Foundation of the Academy of Athens, Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felix","family":"von Zweydorf","sequence":"additional","affiliation":[{"name":"4German Center for Neurodegenerative Diseases, 72076 T\u00fcbingen, Germany"},{"name":"5Institute for Ophthalmic Research, Center for Ophthalmology, University of T\u00fcbingen, T\u00fcbingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saiganesh","family":"Sriraman","sequence":"additional","affiliation":[{"name":"1Department of Cell Biochemistry, University of Groningen, Nijenborgh 7, 9747 AG Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander\u00a0Marc","family":"Thouin","sequence":"additional","affiliation":[{"name":"1Department of Cell Biochemistry, University of Groningen, Nijenborgh 7, 9747 AG Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurine","family":"Vandewynckel","sequence":"additional","affiliation":[{"name":"6Univ. Lille, Inserm, CHU Lille, UMR-S 1172 - LilNCog - Lille Neuroscience & Cognition, F-59000 Lille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William","family":"Sibran","sequence":"additional","affiliation":[{"name":"6Univ. Lille, Inserm, CHU Lille, UMR-S 1172 - LilNCog - Lille Neuroscience & Cognition, F-59000 Lille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie-Christine","family":"Chartier-Harlin","sequence":"additional","affiliation":[{"name":"6Univ. Lille, Inserm, CHU Lille, UMR-S 1172 - LilNCog - Lille Neuroscience & Cognition, F-59000 Lille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R.\u00a0Jeremy","family":"Nichols","sequence":"additional","affiliation":[{"name":"7Department of Structural Biology, St Jud Children\u2019s Research Hospital, Memphis, TN, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisa","family":"Greggio","sequence":"additional","affiliation":[{"name":"8Department of Biology, University of Padova, Padova, Italy"},{"name":"9Centro Studi per la Neurodegenerazione (CESNE), University of Padova, Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Marc","family":"Taymans","sequence":"additional","affiliation":[{"name":"6Univ. Lille, Inserm, CHU Lille, UMR-S 1172 - LilNCog - Lille Neuroscience & Cognition, F-59000 Lille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian\u00a0Johannes","family":"Gloeckner","sequence":"additional","affiliation":[{"name":"4German Center for Neurodegenerative Diseases, 72076 T\u00fcbingen, Germany"},{"name":"5Institute for Ophthalmic Research, Center for Ophthalmology, University of T\u00fcbingen, T\u00fcbingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hardy\u00a0J.","family":"Rideout","sequence":"additional","affiliation":[{"name":"2Center for Clinical, Experimental Surgery, and Translational Research; Biomedical Research Foundation of the Academy of Athens, Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8174-6397","authenticated-orcid":false,"given":"Arjan","family":"Kortholt","sequence":"additional","affiliation":[{"name":"1Department of Cell Biochemistry, University of Groningen, Nijenborgh 7, 9747 AG Groningen, The Netherlands"},{"name":"10YETEM-Innovative Technologies Application and Research Centre Suleyman Demirel University West Campus, Isparta, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2026,6,26]]},"reference":[{"key":"2026052601062935600_B1","doi-asserted-by":"publisher","first-page":"2055","DOI":"10.1016\/S0140-6736(09)60492-X","article-title":"Parkinson\u2019 disease","volume":"373","author":"Lees","year":"2009","journal-title":"Lancet"},{"key":"2026052601062935600_B2","doi-asserted-by":"publisher","first-page":"1042","DOI":"10.1002\/mds.23637","article-title":"Milestones in PD genetics","volume":"26","author":"Gasser","year":"2011","journal-title":"Mov. 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