{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T23:31:05Z","timestamp":1791243065762,"version":"4.1.0"},"reference-count":47,"publisher":"American Society for Clinical Investigation","issue":"19","license":[{"start":{"date-parts":[[2025,10,1]],"date-time":"2025-10-01T00:00:00Z","timestamp":1759276800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Michael J. Fox Foundation for Parkinson\u2019s Research","award":["MJFF #18661,MJFF #15066)"],"award-info":[{"award-number":["MJFF #18661,MJFF #15066)"]}]},{"DOI":"10.13039\/100000065","name":"NINDS","doi-asserted-by":"crossref","award":["P20NS123220"],"award-info":[{"award-number":["P20NS123220"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000918","name":"New York Community Trust","doi-asserted-by":"crossref","award":["P23-000586"],"award-info":[{"award-number":["P23-000586"]}],"id":[{"id":"10.13039\/100000918","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,10,1]]},"abstract":"<jats:p>\n                    LRRK2 contains a kinase domain where the N2081D Crohn\u2019s disease (CD) risk and the G2019S Parkinson\u2019s disease (PD) pathogenic variants are located. It is not clear how the N2081D variant increases CD risk or how these adjacent mutations give rise to distinct disorders. To investigate the pathophysiology of the CD-linked LRRK2 N2081D variant, we generated a knock-in (KI) mouse model and compared its effects with those of the LRRK2-G2019S mutation.\n                    <jats:italic>\n                      Lrrk2\n                      <jats:sup>N2081D<\/jats:sup>\n                    <\/jats:italic>\n                    KI mice demonstrated heightened sensitivity to induced colitis, resulting in more severe intestinal damage than in\n                    <jats:italic>\n                      Lrrk2\n                      <jats:sup>G2019S<\/jats:sup>\n                    <\/jats:italic>\n                    KI and WT mice. Analysis of colon tissue revealed distinct mutation-dependent LRRK2 RAB substrate phosphorylation, with significantly elevated phosphorylated RAB10 levels in\n                    <jats:italic>\n                      Lrrk2\n                      <jats:sup>N2081D<\/jats:sup>\n                    <\/jats:italic>\n                    mice. In cells, we demonstrated that the N2081D mutation activates LRRK2 through a mechanism distinct from that of LRRK2-G2019S. We also found that proinflammatory stimulation enhances LRRK2 kinase activity, leading to mutation-dependent differences in RAB phosphorylation and inflammatory responses in dendritic cells (DCs). Finally, we show that knockout of\n                    <jats:italic>Rab12<\/jats:italic>\n                    , but not pharmacological LRRK2 kinase inhibition, significantly reduced colitis severity in\n                    <jats:italic>\n                      Lrrk2\n                      <jats:sup>N2081D<\/jats:sup>\n                    <\/jats:italic>\n                    mice. Our study characterizes the pathogenic mechanisms of LRRK2-linked CD, highlights structural and functional differences between disease-associated LRRK2 variants, and suggests RAB proteins as promising therapeutic targets for modulating LRRK2 activity in CD treatment.\n                  <\/jats:p>","DOI":"10.1172\/jci190017","type":"journal-article","created":{"date-parts":[[2025,9,30]],"date-time":"2025-09-30T18:01:01Z","timestamp":1759255261000},"source":"Crossref","is-referenced-by-count":4,"title":["Targeting specific kinase substrates rescues increased colitis severity induced by the Crohn\u2019s disease\u2013linked LRRK2-N2081D variant"],"prefix":"10.1172","volume":"135","author":[{"given":"George R.","family":"Heaton","sequence":"first","affiliation":[{"name":"Center for Parkinson\u2019s Disease Neurobiology, Departments of Neurology and Neuroscience, The Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingjian","family":"Li","sequence":"additional","affiliation":[{"name":"Center for Parkinson\u2019s Disease Neurobiology, Departments of Neurology and Neuroscience, The Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xianting","family":"Li","sequence":"additional","affiliation":[{"name":"Center for Parkinson\u2019s Disease Neurobiology, Departments of Neurology and Neuroscience, The Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoting","family":"Zhou","sequence":"additional","affiliation":[{"name":"Center for Parkinson\u2019s Disease Neurobiology, Departments of Neurology and Neuroscience, The Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanxi","family":"Zhang","sequence":"additional","affiliation":[{"name":"Center for Parkinson\u2019s Disease Neurobiology, Departments of Neurology and Neuroscience, The Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Duc Tung","family":"Vu","sequence":"additional","affiliation":[{"name":"Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc","family":"Oeller","sequence":"additional","affiliation":[{"name":"Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ozge","family":"Karayel","sequence":"additional","affiliation":[{"name":"Proteomics and Signal Transduction, Max Planck Institute of 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