{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T22:29:03Z","timestamp":1786660143345,"version":"build-2736575974"},"posted":{"date-parts":[[2026,6,10]]},"group-title":"Immunology","reference-count":34,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T00:00:00Z","timestamp":1781049600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,8,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  The LRRK2 G2019S mutation is one of the most common genetic risk factors for Parkinson\u2019s disease (PD), yet LRRK2 G2019S knock-in (KI) mice rarely develop robust neurodegeneration under basal conditions, suggesting that additional environmental triggers are required for disease progression. Here, we established a clinically relevant gene\u2013environment interaction mouse model of PD by subjecting LRRK2 G2019S KI mice to recurrent\n                  <jats:italic>Citrobacter (C.) rodentium<\/jats:italic>\n                  infection, a murine model of enteric bacterial inflammation. Repeated infection induced progressive PD-like phenotypes selectively in KI mice, including motor impairment, reduced locomotor activity, impaired motor coordination, selective nigrostriatal dopaminergic neurodegeneration, enhanced neuroinflammation, and pathological phosphorylated \u03b1-synuclein (p-\u03b1Syn) accumulation, whereas wild-type (WT) mice remained largely resistant. Mechanistically, infected KI mice developed markedly exacerbated colonic inflammation, epithelial barrier dysfunction, increased intestinal permeability, and enhanced inflammasome activation despite normal bacterial clearance, indicating that pathogenic LRRK2 signaling amplifies inflammatory responses rather than impairing antimicrobial defense. In parallel, recurrent infection induced pronounced intestinal p-\u03b1Syn accumulation and expansion of pathology beyond the epithelial layer in KI mice, supporting a gut\u2013brain axis mechanism linking intestinal inflammation to neurodegeneration. Collectively, these findings demonstrate that the LRRK2 G2019S mutation functions as a sensitizing factor that cooperates with recurrent enteric inflammation to drive PD- related pathology. This study establishes a physiologically relevant LRRK2 G2019S gene\u2013 environment interaction mouse model that recapitulates key behavioral, neuropathological, and inflammatory features of PD.\n                <\/jats:p>","DOI":"10.64898\/2026.06.08.728789","type":"posted-content","created":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T01:35:20Z","timestamp":1781141720000},"source":"Crossref","is-referenced-by-count":0,"title":["Gut bacterial Infection drives Parkinsonian pathology in LRRK2 G2019S Knock-in Mice"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-9915-9121","authenticated-orcid":false,"given":"Yuhang","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0488-1792","authenticated-orcid":false,"given":"Matthew A.","family":"Weber","sequence":"additional","affiliation":[{"name":"Department of Neurology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nick C","family":"Stodden","sequence":"additional","affiliation":[{"name":"Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lily M","family":"Ziebarth","sequence":"additional","affiliation":[{"name":"Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sivakumar","family":"Lingappa","sequence":"additional","affiliation":[{"name":"Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monserrath A","family":"Borjabustamante","sequence":"additional","affiliation":[{"name":"Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tharoon A","family":"Balakrishnan","sequence":"additional","affiliation":[{"name":"Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manab","family":"Jaily","sequence":"additional","affiliation":[{"name":"Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taylor","family":"Sakaguchi","sequence":"additional","affiliation":[{"name":"Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramasamy","family":"Thangavel","sequence":"additional","affiliation":[{"name":"Department of Neurology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6911-0967","authenticated-orcid":false,"given":"Wen","family":"Wen","sequence":"additional","affiliation":[{"name":"Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6968-3618","authenticated-orcid":false,"given":"Jia","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0427-0003","authenticated-orcid":false,"given":"Nandakumar S.","family":"Narayanan","sequence":"additional","affiliation":[{"name":"Department of Neurology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA"},{"name":"Iowa Neuroscience Institute, University of Iowa, Iowa City, IA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5621-8912","authenticated-orcid":false,"given":"Zizhen","family":"Kang","sequence":"additional","affiliation":[{"name":"Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"issue":"10","key":"2026081315150780000_2026.06.08.728789v2.1","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1016\/S1474-4422(20)30320-3","article-title":"Developing therapies for Parkinson\u2019s disease","volume":"19","author":"The Lancet N.","year":"2020","journal-title":"Lancet Neurol"},{"key":"2026081315150780000_2026.06.08.728789v2.2","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(18)30295-3"},{"key":"2026081315150780000_2026.06.08.728789v2.3","doi-asserted-by":"crossref","unstructured":"Patrick KL , Bell SL , Weindel CG , Watson RO . 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