{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T14:00:41Z","timestamp":1785420041403,"version":"3.56.0"},"posted":{"date-parts":[[2026,4,27]]},"group-title":"Neuroscience","reference-count":50,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,4,27]],"date-time":"2026-04-27T00:00:00Z","timestamp":1777248000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"award":["R01NS120489"],"award-info":[{"award-number":["R01NS120489"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,4,27]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Mutations in the\n                  <jats:italic>LRRK2<\/jats:italic>\n                  gene are the most frequent cause of familial Parkinson\u2019s disease (PD) whereas common variants are associated with an increased risk for sporadic PD.\n                  <jats:italic>LRRK2<\/jats:italic>\n                  encodes a multi-domain protein displaying two functional enzymatic activities: GTPase and kinase. Familial\n                  <jats:italic>LRRK2<\/jats:italic>\n                  mutations have been linked to alterations in its GTPase and kinase activities, elevated substrate phosphorylation, as well as increased neurotoxicity in cell and animal models. In addition to familial mutations, several common\n                  <jats:italic>LRRK2<\/jats:italic>\n                  coding variants have been associated with PD risk in different ethnic populations. Little is known about how these coding variants modulate the risk of developing PD. In this study, we aim to evaluate whether a collection of\n                  <jats:italic>LRRK2<\/jats:italic>\n                  coding risk variants (A419V, N551K, R1398H, R1628P, M1646T, S1647T, G2385R) modify the biochemical properties of the LRRK2 protein and LRRK2-mediated neurotoxicity using cell-based assays. With the exception of G2385R, we find that coding risk variants have minimal impact on LRRK2 steady-state protein levels, GTP-binding, phosphorylation at Ser910, Ser935, and Ser1292, and subcellular localization in human cell lines and cultured primary neurons. G2385R reduces the steady-state levels of LRRK2 and exhibits reduced phosphorylation at Ser910\/Ser935 and Ser1292, consistent with diminished kinase activity. Notably, however,\n                  <jats:italic>LRRK2<\/jats:italic>\n                  variants associated with increased PD risk (A419V, R1628P, M1646T, and G2385R) significantly elevate the levels of LRRK2-mediated Rab10 phosphorylation by two-fold in cells. In contrast,\n                  <jats:italic>LRRK2<\/jats:italic>\n                  variants associated with reduced PD risk (N551K, R1398H, and N551K-R1398H) do not alter normal LRRK2-mediated pRab10 levels. Intriguingly, we find that both PD-risk and PD-protective LRRK2 variants can respond normally to kinase activation by different lysosomal stressors (chloroquine, nigericin and monensin) to robustly induce pRab10 levels in cells. The PD risk variant, G2385R LRRK2, significantly inhibits neurite outgrowth in primary cortical neurons compared to wild-type LRRK2. Combining each coding risk variant with the familial G2019S mutation has minimal impact on the elevated kinase activity of G2019S LRRK2 or its capacity to inhibit neurite outgrowth. Our study indicates that LRRK2-dependent Rab phosphorylation represents a relevant readout of PD risk induced by\n                  <jats:italic>LRRK2<\/jats:italic>\n                  coding variants and demonstrates that the PD risk variant, G2385R LRRK2, creates a hyperactive kinase that can impair neuronal integrity at comparable levels to the effects of G2019S LRRK2.\n                <\/jats:p>","DOI":"10.64898\/2026.04.23.720426","type":"posted-content","created":{"date-parts":[[2026,4,27]],"date-time":"2026-04-27T22:30:13Z","timestamp":1777329013000},"source":"Crossref","is-referenced-by-count":0,"title":["Parkinson\u2019s disease-associated LRRK2 risk variant, G2385R, enhances Rab substrate phosphorylation and impairs neuronal integrity"],"prefix":"10.64898","author":[{"given":"An Phu Tran","family":"Nguyen","sequence":"first","affiliation":[{"name":"Departments of Neurodegenerative Science, Van Andel Institute, Grand Rapids, Michigan 49503, USA"},{"name":"Department of Biological Sciences, University of Wisconsin-Milwaukee, Milwaukee, WI 53211, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roger","family":"Moser","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Neurodegenerative Research, Brain Mind Institute, Swiss Federal Institute of Technology (EPFL), 1015 Lausanne, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole","family":"Bryant","sequence":"additional","affiliation":[{"name":"Center for Neurodegeneration and Neurotherapeutics, Duke University, Durham, NC 27710, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lindsey A.","family":"Cunningham","sequence":"additional","affiliation":[{"name":"Departments of Neurodegenerative Science, Van Andel Institute, Grand Rapids, Michigan 49503, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evan J.","family":"Worden","sequence":"additional","affiliation":[{"name":"Departments of Structural Biology, Van Andel Institute, Grand Rapids, Michigan 49503, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2359-5679","authenticated-orcid":false,"given":"Darren J.","family":"Moore","sequence":"additional","affiliation":[{"name":"Departments of Neurodegenerative Science, Van Andel Institute, Grand Rapids, Michigan 49503, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026043004151507000_2026.04.23.720426v1.1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2004.10.023"},{"key":"2026043004151507000_2026.04.23.720426v1.2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2004.11.005"},{"key":"2026043004151507000_2026.04.23.720426v1.3","doi-asserted-by":"publisher","DOI":"10.1002\/ana.20664"},{"key":"2026043004151507000_2026.04.23.720426v1.4","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(05)17829-5"},{"key":"2026043004151507000_2026.04.23.720426v1.5","doi-asserted-by":"publisher","DOI":"10.1086\/432422"},{"key":"2026043004151507000_2026.04.23.720426v1.6","doi-asserted-by":"publisher","DOI":"10.1212\/01.WNL.0000167552.79769.b3"},{"key":"2026043004151507000_2026.04.23.720426v1.7","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddi376"},{"key":"2026043004151507000_2026.04.23.720426v1.8","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2021.05.004"},{"key":"2026043004151507000_2026.04.23.720426v1.9","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1007\/978-3-319-49969-7_4","article-title":"Understanding the GTPase Activity of LRRK2: Regulation, Function, and Neurotoxicity","volume":"14","year":"2017","journal-title":"Adv Neurobiol"},{"key":"2026043004151507000_2026.04.23.720426v1.10","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3004485"},{"key":"2026043004151507000_2026.04.23.720426v1.11","doi-asserted-by":"crossref","unstructured":"Steger, M. , et al., Phosphoproteomics reveals that Parkinson\u2019s disease kinase LRRK2 regulates a subset of Rab GTPases. Elife, 2016. 5.","DOI":"10.7554\/eLife.12813"},{"key":"2026043004151507000_2026.04.23.720426v1.12","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.08.004"},{"key":"2026043004151507000_2026.04.23.720426v1.13","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20100483"},{"key":"2026043004151507000_2026.04.23.720426v1.14","doi-asserted-by":"publisher","DOI":"10.1042\/BCJ20210375"},{"key":"2026043004151507000_2026.04.23.720426v1.15","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-biochem-030122-051144"},{"key":"2026043004151507000_2026.04.23.720426v1.16","doi-asserted-by":"crossref","unstructured":"Bonet-Ponce, L. , et al., LRRK2 mediates tubulation and vesicle sorting from lysosomes. Sci Adv, 2020. 6(46).","DOI":"10.1126\/sciadv.abb2454"},{"key":"2026043004151507000_2026.04.23.720426v1.17","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1812196115"},{"key":"2026043004151507000_2026.04.23.720426v1.18","doi-asserted-by":"publisher","DOI":"10.15252\/embj.2020104494"},{"key":"2026043004151507000_2026.04.23.720426v1.19","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2020.105081"},{"key":"2026043004151507000_2026.04.23.720426v1.20","doi-asserted-by":"publisher","DOI":"10.1042\/BST20160264"},{"key":"2026043004151507000_2026.04.23.720426v1.21","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.abq7374"},{"issue":"6","key":"2026043004151507000_2026.04.23.720426v1.22","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1093\/hmg\/ddab058","article-title":"Identification of LRRK2 missense variants in the accelerating medicines partnership Parkinson\u2019s disease cohort","volume":"30","year":"2021","journal-title":"Hum Mol Genet"},{"key":"2026043004151507000_2026.04.23.720426v1.23","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(11)70175-2"},{"key":"2026043004151507000_2026.04.23.720426v1.24","doi-asserted-by":"publisher","DOI":"10.1007\/s10048-006-0041-5"},{"key":"2026043004151507000_2026.04.23.720426v1.25","doi-asserted-by":"publisher","DOI":"10.1212\/01.WNL.0000169023.51764.b0"},{"key":"2026043004151507000_2026.04.23.720426v1.26","doi-asserted-by":"publisher","DOI":"10.3389\/fnagi.2019.00013"},{"key":"2026043004151507000_2026.04.23.720426v1.27","doi-asserted-by":"crossref","unstructured":"Christensen, K.V. , Hentzer, M. , Oppermann, F. S. , Elschenbroich, S. , Dossang, P. , Thirstrup, K. , Egebjerg, J. , Williamson, D. S. , Smith, G. P. , LRRK2 exonic variants associated with Parkinson\u2019s disease augment phosphorylation levels for LRRK2-Ser1292 and Rab10-Thr73. bioRxiv, 2018.","DOI":"10.1101\/447946"},{"key":"2026043004151507000_2026.04.23.720426v1.28","doi-asserted-by":"crossref","unstructured":"Hui, K.Y. , et al., Functional variants in the LRRK2 gene confer shared effects on risk for Crohn\u2019s disease and Parkinson\u2019s disease. Sci Transl Med, 2018. 10(423).","DOI":"10.1126\/scitranslmed.aai7795"},{"key":"2026043004151507000_2026.04.23.720426v1.29","doi-asserted-by":"publisher","DOI":"10.1042\/bcj20220161"},{"key":"2026043004151507000_2026.04.23.720426v1.30","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/dds522"},{"key":"2026043004151507000_2026.04.23.720426v1.31","doi-asserted-by":"publisher","DOI":"10.3389\/fnmol.2016.00018"},{"key":"2026043004151507000_2026.04.23.720426v1.32","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddx161"},{"key":"2026043004151507000_2026.04.23.720426v1.33","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddr526"},{"key":"2026043004151507000_2026.04.23.720426v1.34","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1002526"},{"key":"2026043004151507000_2026.04.23.720426v1.35","unstructured":"Toh, T.S. , et al., Ex Vivo LRRK2 Activation in Asian G2385R and R1628P Variant Carriers and Idiopathic Parkinson\u2019s Disease. Mov Disord, 2026."},{"key":"2026043004151507000_2026.04.23.720426v1.36","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-021-91943-4"},{"key":"2026043004151507000_2026.04.23.720426v1.37","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20070209"},{"key":"2026043004151507000_2026.04.23.720426v1.38","doi-asserted-by":"publisher","DOI":"10.1007\/s11064-018-2650-4"},{"key":"2026043004151507000_2026.04.23.720426v1.39","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20120637"},{"key":"2026043004151507000_2026.04.23.720426v1.40","doi-asserted-by":"publisher","DOI":"10.1042\/BCJ20180589"},{"key":"2026043004151507000_2026.04.23.720426v1.41","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1817889116"},{"key":"2026043004151507000_2026.04.23.720426v1.42","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0008463"},{"key":"2026043004151507000_2026.04.23.720426v1.43","doi-asserted-by":"crossref","unstructured":"Lara Ordonez, A.J. , et al., The LRRK2 signaling network converges on a centriolar phospho-Rab10\/RILPL1 complex to cause deficits in centrosome cohesion and cell polarization. Biol Open, 2022. 11(8).","DOI":"10.1242\/bio.059468"},{"key":"2026043004151507000_2026.04.23.720426v1.44","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-05760-9"},{"key":"2026043004151507000_2026.04.23.720426v1.45","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.00914-13"},{"key":"2026043004151507000_2026.04.23.720426v1.46","doi-asserted-by":"crossref","first-page":"754956","DOI":"10.3389\/fnagi.2021.754956","article-title":"Curcumin Reduced H(2)O(2)- and G2385R-LRRK2-Induced Neurodegeneration","volume":"13","year":"2021","journal-title":"Front Aging Neurosci"},{"key":"2026043004151507000_2026.04.23.720426v1.47","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1922184117"},{"key":"2026043004151507000_2026.04.23.720426v1.48","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0508052102"},{"key":"2026043004151507000_2026.04.23.720426v1.49","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddx410"},{"key":"2026043004151507000_2026.04.23.720426v1.50","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddy224"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.04.23.720426","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T11:15:26Z","timestamp":1777547726000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.64898\/2026.04.23.720426"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,27]]},"references-count":50,"URL":"https:\/\/doi.org\/10.64898\/2026.04.23.720426","relation":{},"subject":[],"published":{"date-parts":[[2026,4,27]]},"subtype":"preprint"}}