{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T19:33:43Z","timestamp":1786390423577,"version":"build-2736575974"},"reference-count":96,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"47","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Adv."],"published-print":{"date-parts":[[2024,11,22]]},"abstract":"<jats:p>\n            Mutations in\n            <jats:italic>LRRK2<\/jats:italic>\n            are the most common genetic cause of Parkinson\u2019s disease (PD). LRRK2 protein contains two enzymatic domains: a GTPase (Roc-COR) and a kinase domain. Disease-causing mutations are found in both domains. Now, studies have focused largely on LRRK2 kinase activity, while attention to its GTPase function is limited. LRRK2 is a guanine nucleotide\u2013binding protein, but the mechanism of direct regulation of its GTPase activity remains unclear and its physiological GEF is not known. Here, we identified CalDAG-GEFI (CDGI) as a physiological GEF for LRRK2. CDGI interacts with LRRK2 and increases its GDP to GTP exchange activity. CDGI modulates LRRK2 cellular functions and LRRK2-induced neurodegeneration in both LRRK2\n            <jats:italic>Drosophila<\/jats:italic>\n            and mouse models. Together, this study identified the physiological GEF for LRRK2 and provides strong evidence that LRRK2 GTPase is regulated by GAPs and GEFs. The LRRK2 GTPase, GAP, or GEF activities have the potential to serve as therapeutic targets, which is distinct from the direct LRRK2 kinase inhibition.\n          <\/jats:p>","DOI":"10.1126\/sciadv.adn5417","type":"journal-article","created":{"date-parts":[[2024,11,22]],"date-time":"2024-11-22T19:10:42Z","timestamp":1732302642000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":4,"title":["CalDAG-GEFI acts as a guanine nucleotide exchange factor for LRRK2 to regulate LRRK2 function and neurodegeneration"],"prefix":"10.1126","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2930-3892","authenticated-orcid":true,"given":"Qinfang","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Neuroscience, University of Connecticut School of Medicine, Farmington, CT 06030, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bingxu","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, University of Connecticut School of Medicine, Farmington, CT 06030, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noah Guy Lewis","family":"Guiberson","sequence":"additional","affiliation":[{"name":"Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA."},{"name":"Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shifan","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, University of Connecticut School of Medicine, Farmington, CT 06030, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-2741-7160","authenticated-orcid":true,"given":"Dong","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, University of Connecticut School of Medicine, Farmington, CT 06030, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gang","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Physiology and Neurobiology, University of Connecticut, Storrs, CT 06269, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin-Ming","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, University of Connecticut School of Medicine, Farmington, CT 06030, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jill R.","family":"Crittenden","sequence":"additional","affiliation":[{"name":"McGovern Institute for Brain Research and Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA."},{"name":"Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4883-646X","authenticated-orcid":true,"given":"Jianzhong","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Physiology and Neurobiology, University of Connecticut, Storrs, CT 06269, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4326-7720","authenticated-orcid":true,"given":"Ann M.","family":"Graybiel","sequence":"additional","affiliation":[{"name":"McGovern Institute for Brain Research and Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6459-0893","authenticated-orcid":true,"given":"Ted M.","family":"Dawson","sequence":"additional","affiliation":[{"name":"Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA."},{"name":"Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA."},{"name":"Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA."},{"name":"Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA."},{"name":"Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2915-3970","authenticated-orcid":true,"given":"Valina L.","family":"Dawson","sequence":"additional","affiliation":[{"name":"Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA."},{"name":"Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA."},{"name":"Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA."},{"name":"Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130, USA."},{"name":"Diana Helis Henry Medical Research Foundation, New Orleans, LA 70130, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1649-7552","authenticated-orcid":true,"given":"Yulan","family":"Xiong","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, University of Connecticut School of Medicine, Farmington, CT 06030, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(09)60492-X"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.202012095"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrn2935"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tins.2006.03.006"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1000902"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1042\/BST20120093"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4566-11.2012"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/nn1776"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1002\/mds.26075"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1002\/mds.26647"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0507360102"},{"key":"e_1_3_2_13_2","first-page":"541","article-title":"LRRK2 functions in synaptic vesicle endocytosis through a kinase-dependent mechanism","volume":"128","author":"Arranz A. M.","year":"2015","unstructured":"A. M. Arranz, L. Delbroek, K. Van Kolen, M. R. Guimaraes, W. Mandemakers, G. Daneels, S. Matta, S. Calafate, H. Shaban, P. Baatsen, P. J. De Bock, K. Gevaert, P. Vanden Berghe, P. Verstreken, B. De Strooper, D. Moechars, LRRK2 functions in synaptic vesicle endocytosis through a kinase-dependent mechanism. J. Cell. Sci. 128, 541\u2013552 (2015).","journal-title":"J. Cell. Sci."},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13024-015-0066-z"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11910-015-0564-y"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M115.660001"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2006.04.001"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddr348"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20070209"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.12813"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2014.01.064"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aar5429"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.abj2658"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.abg3555"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1717590115"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0013762"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddu202"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1002526"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1038\/nchembio.538"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1186\/1476-4598-13-103"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2013.02.041"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.2174\/156802661510150328223655"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.2174\/1570159X13666151030102847"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tibs.2022.06.009"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceb.2010.04.007"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrm2689"},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.1038\/emboj.2008.150"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1323285111"},{"key":"e_1_3_2_39_2","doi-asserted-by":"publisher","DOI":"10.1111\/jnc.14566"},{"key":"e_1_3_2_40_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.22.13278"},{"key":"e_1_3_2_41_2","doi-asserted-by":"publisher","DOI":"10.1002\/ana.21019"},{"key":"e_1_3_2_42_2","doi-asserted-by":"publisher","DOI":"10.1002\/ana.20808"},{"key":"e_1_3_2_43_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neulet.2008.06.086"},{"key":"e_1_3_2_44_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.2006.04246.x"},{"key":"e_1_3_2_45_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2006.01.017"},{"key":"e_1_3_2_46_2","doi-asserted-by":"publisher","DOI":"10.1002\/cne.23583"},{"key":"e_1_3_2_47_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymeth.2005.05.015"},{"key":"e_1_3_2_48_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2015-11-683102"},{"key":"e_1_3_2_49_2","doi-asserted-by":"publisher","DOI":"10.1093\/biomethods\/bpab024"},{"key":"e_1_3_2_50_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0907725106"},{"key":"e_1_3_2_51_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi100157u"},{"key":"e_1_3_2_52_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.adi9926"},{"key":"e_1_3_2_53_2","doi-asserted-by":"publisher","DOI":"10.15252\/embj.201798099"},{"key":"e_1_3_2_54_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddx410"},{"key":"e_1_3_2_55_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2012.11.033"},{"key":"e_1_3_2_56_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.87098"},{"key":"e_1_3_2_57_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.87255"},{"key":"e_1_3_2_58_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2023.105192"},{"key":"e_1_3_2_59_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200312034"},{"key":"e_1_3_2_60_2","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abb2454"},{"key":"e_1_3_2_61_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1812196115"},{"key":"e_1_3_2_62_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2012.07.017"},{"key":"e_1_3_2_63_2","doi-asserted-by":"publisher","DOI":"10.1002\/cne.1291"},{"key":"e_1_3_2_64_2","doi-asserted-by":"publisher","DOI":"10.1523\/ENEURO.0004-17.2017"},{"key":"e_1_3_2_65_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(00)80886-7"},{"key":"e_1_3_2_66_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0773.1990.tb00833.x"},{"key":"e_1_3_2_67_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.287.5456.1265"},{"key":"e_1_3_2_68_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0306-4522(01)00295-0"},{"key":"e_1_3_2_69_2","doi-asserted-by":"publisher","DOI":"10.1002\/mds.21010"},{"key":"e_1_3_2_70_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms19124074"},{"key":"e_1_3_2_71_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-319-49969-7_4"},{"key":"e_1_3_2_72_2","doi-asserted-by":"publisher","DOI":"10.1042\/BST20120133"},{"key":"e_1_3_2_73_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-017-01103-4"},{"key":"e_1_3_2_74_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.2009.06358.x"},{"key":"e_1_3_2_75_2","doi-asserted-by":"publisher","DOI":"10.1096\/fj.15-277095"},{"key":"e_1_3_2_76_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2020.08.002"},{"key":"e_1_3_2_77_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2012.10.027"},{"key":"e_1_3_2_78_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddr481"},{"key":"e_1_3_2_79_2","first-page":"232","article-title":"Dysregulation of lysosomal morphology by pathogenic LRRK2 is corrected by TPC2 inhibition","volume":"128","author":"Hockey L. N.","year":"2015","unstructured":"L. N. Hockey, B. S. Kilpatrick, E. R. Eden, Y. Lin-Moshier, G. C. Brailoiu, E. Brailoiu, C. E. Futter, A. H. Schapira, J. S. Marchant, S. Patel, Dysregulation of lysosomal morphology by pathogenic LRRK2 is corrected by TPC2 inhibition. J. Cell Sci. 128, 232\u2013238 (2015).","journal-title":"J. Cell Sci."},{"key":"e_1_3_2_80_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.stemcr.2018.11.021"},{"key":"e_1_3_2_81_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-019-1469-5"},{"key":"e_1_3_2_82_2","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awad064"},{"key":"e_1_3_2_83_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11064-021-03464-1"},{"key":"e_1_3_2_84_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddq055"},{"key":"e_1_3_2_85_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0812822106"},{"key":"e_1_3_2_86_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13041-016-0234-2"},{"key":"e_1_3_2_87_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.89.9.3859"},{"key":"e_1_3_2_88_2","doi-asserted-by":"publisher","DOI":"10.3390\/cells9112344"},{"key":"e_1_3_2_89_2","doi-asserted-by":"publisher","DOI":"10.15252\/embj.2022113410"},{"key":"e_1_3_2_90_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aba1659"},{"key":"e_1_3_2_91_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3314-15.2016"},{"key":"e_1_3_2_92_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1004676107"},{"key":"e_1_3_2_93_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm1098"},{"key":"e_1_3_2_94_2","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.2089"},{"key":"e_1_3_2_95_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddl471"},{"key":"e_1_3_2_96_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1712648115"},{"key":"e_1_3_2_97_2","unstructured":"G. Paxinos K. B. J. Franklin The Mouse Brain in Stereotaxic Coordinates (Elsevier Academic Press Boston ed. Compact 2nd 2004)."}],"container-title":["Science Advances"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.science.org\/doi\/pdf\/10.1126\/sciadv.adn5417","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,11,22]],"date-time":"2024-11-22T19:12:07Z","timestamp":1732302727000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.science.org\/doi\/10.1126\/sciadv.adn5417"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,11,22]]},"references-count":96,"journal-issue":{"issue":"47","published-print":{"date-parts":[[2024,11,22]]}},"alternative-id":["10.1126\/sciadv.adn5417"],"URL":"https:\/\/doi.org\/10.1126\/sciadv.adn5417","relation":{},"ISSN":["2375-2548"],"issn-type":[{"value":"2375-2548","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,11,22]]},"assertion":[{"value":"2023-12-14","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-10-22","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-11-22","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"eadn5417"}}