{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T04:13:27Z","timestamp":1791346407299,"version":"4.3.1"},"reference-count":68,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T00:00:00Z","timestamp":1776643200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T00:00:00Z","timestamp":1776643200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100000864","name":"Michael J. Fox Foundation for Parkinson's Research","doi-asserted-by":"publisher","award":["MJFF\u2010010188"],"award-info":[{"award-number":["MJFF\u2010010188"]}],"id":[{"id":"10.13039\/100000864","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000864","name":"Michael J. 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Fox Foundation for Parkinson's Research","doi-asserted-by":"publisher","award":["MJFF\u2010022659"],"award-info":[{"award-number":["MJFF\u2010022659"]}],"id":[{"id":"10.13039\/100000864","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["movementdisorders.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Movement Disorders"],"published-print":{"date-parts":[[2026,7]]},"abstract":"Abstract<\/jats:title>\n \n Background<\/jats:title>\n \n Leucine\u2010rich repeat kinase 2 (LRRK2) kinase inhibition is a promising therapeutic strategy for Parkinson's disease (PD), but the functional impact of Asian\u2010prevalent\n LRRK2<\/jats:italic>\n p.G2385R and p.R1628P variants remains unclear. Robust patient stratification and target engagement markers are needed for global LRRK2\u2010targeted trials.\n <\/jats:p>\n <\/jats:sec>\n \n Objective<\/jats:title>\n \n The aim of this study was to characterize ex vivo LRRK2 activation status and its clinical correlates in patients with PD carrying\n LRRK2<\/jats:italic>\n p.G2385R and\/or p.R1628P variants and in patients with idiopathic PD (iPD).\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n We recruited 242 participants: patients with PD carrying\n LRRK2<\/jats:italic>\n p.G2385R (PD\u2010G2385R; n\u2009=\u200957), p.R1628P (PD\u2010R1628P; n\u2009=\u200961), or both (n\u2009=\u20095); patients with iPD (n\u2009=\u200961); and healthy control subjects (HCs; n\u2009=\u200958). Monocyte LRRK2 activity markers (pRab10\n Thr73<\/jats:sup>\n and pLRRK2\n Ser935<\/jats:sup>\n ) were analyzed using multiplexed quantitative immunoblotting. Clinical severity was assessed using the International Parkinson and Movement Disorder Society\u2010Unified Parkinson's Disease Rating Scale, Clinical Impression of Severity Index for PD, and Montreal Cognitive Assessment.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Compared with HCs, pRab10\n Thr73<\/jats:sup>\n was elevated (indicative of LRRK2 kinase hyperactivation) in PD\u2010G2385R (~1.2\u2010fold,\n P<\/jats:italic>\n \u2009=\u20090.011) and in double\u2010variant carriers (~2.8\u2010fold,\n P<\/jats:italic>\n \u2009=\u20090.008), but not in PD\u2010R1628P or iPD. Inversely correlated with pRab10\n Thr73<\/jats:sup>\n (\n r<\/jats:italic>\n \n s<\/jats:italic>\n <\/jats:sub>\n \u2009=\u2009\u22120.611,\n P<\/jats:italic>\n \u2009<\u20090.001), pLRRK2\n Ser935<\/jats:sup>\n was reduced (indicative of a more active LRRK2 conformation) in all PD subgroups (lowest in double\u2010variant carriers). All double\u2010variant carriers, the majority of single\u2010variant carriers, and one\u2010third of participants with iPD had pRab10\n Thr73<\/jats:sup>\n greater than the control median. Higher pRab10\n Thr73<\/jats:sup>\n correlated with better cognition.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n \n LRRK2 kinase activity is enhanced in patients with PD carrying\u00a0\n LRRK2<\/jats:italic>\n p.G2385R, with further elevation observed in a small group of double\u2010variant carriers. Elevated kinase activity in a subset of iPD underscores the relevance of LRRK2 signaling and therapeutics beyond coding variants. The observed interindividual variability indicates additional genetic or environmental modifiers and highlights the need for biochemical stratification beyond genotyping in future LRRK2 trials. \u00a9 2026 The Author(s).\n Movement Disorders<\/jats:italic>\n published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1002\/mds.70314","type":"journal-article","created":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T10:56:12Z","timestamp":1776682572000},"page":"1750-1761","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Ex Vivo\n LRRK2<\/scp>\n Activation in Asian\n G2385R<\/scp>\n and\n R1628P<\/scp>\n Variant Carriers and Idiopathic Parkinson's Disease"],"prefix":"10.1002","volume":"41","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2434-2147","authenticated-orcid":false,"given":"Tzi 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