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Although LRRK2 kinase inhibitors are advancing clinically, non-invasive readouts of LRRK2-linked pathway modulation remain limited. Profiling urinary proteomes from 1215 individuals across three cohorts and integrating whole-genome sequencing from &gt;500 participants to map genotype\u2013proteome associations, we identified 177 urinary proteins associated with pathogenic LRRK2, enriched for lysosomal\/glycosphingolipid, immune, and membrane-trafficking pathways. Machine learning narrowed the features to a cohort-agnostic 30-protein panel that classified G2019S carriers with a mean ROC AUC of 0.91 across independent tests. To evaluate translation, we performed multi-organ and urinary proteomics in rat gain- and loss-of-function models (BAC-\n                    <jats:italic>LRRK2<\/jats:italic>\n                    <jats:sup>G2019S<\/jats:sup>\n                    and\n                    <jats:italic>Lrrk2<\/jats:italic>\n                    <jats:sup>KO<\/jats:sup>\n                    ) and after Lrrk2 inhibition (MLi-2 and PF-475), revealing tissue-specific responses\u2014strongest in kidney\u2014and cross-species overlap, including 24 brain proteins detectable in human urine. Rat-derived perturbations predicted\n                    <jats:italic>LRRK2<\/jats:italic>\n                    mutation status in patients (AUC 0.75) and reversed with Lrrk2 inhibition, supporting their pharmacodynamic utility. Together, our findings establish urine as a scalable, non-invasive matrix that captures systemic and brain-relevant consequences of LRRK2 dysfunction and nominate candidate pharmacodynamic markers set to support LRRK2-directed trials.\n                  <\/jats:p>","DOI":"10.1038\/s44320-026-00190-0","type":"journal-article","created":{"date-parts":[[2026,1,29]],"date-time":"2026-01-29T10:55:29Z","timestamp":1769684129000},"page":"712-737","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Multi-cohort, cross-species urinary proteomics reveals signatures of LRRK2 dysfunction in Parkinson\u2019s disease"],"prefix":"10.1038","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7573-1591","authenticated-orcid":false,"given":"Duc Tung","family":"Vu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William","family":"Sibran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1043-6591","authenticated-orcid":false,"given":"Andreas","family":"Metousis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurine","family":"Vandewynckel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Basak","family":"Eraslan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0925-5870","authenticated-orcid":false,"given":"Liesel","family":"Goveas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3387-2537","authenticated-orcid":false,"given":"Ericka CM","family":"Itang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claire","family":"Deldycke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2913-9589","authenticated-orcid":false,"given":"Adriana","family":"Figueroa-Garcia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R\u00e9ginald","family":"Lef\u00e8bvre","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3454-2396","authenticated-orcid":false,"given":"Johannes Bruno","family":"M\u00fcller-Reif","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2299-8110","authenticated-orcid":false,"given":"Sebastian","family":"Virreira Winter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6416-6526","authenticated-orcid":false,"given":"Marie-Christine","family":"Chartier-Harlin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5503-5524","authenticated-orcid":false,"given":"Jean-Marc","family":"Taymans","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1292-4799","authenticated-orcid":false,"given":"Matthias","family":"Mann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2541-1159","authenticated-orcid":false,"given":"Ozge","family":"Karayel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,1,29]]},"reference":[{"key":"190_CR1","doi-asserted-by":"publisher","first-page":"1099","DOI":"10.1586\/ern.11.96","volume":"11","author":"M Aerts","year":"2011","unstructured":"Aerts M, Meijer FJ, Verbeek M, Esselink R, Bloem BR (2011) Diagnostic challenges in parkinsonism. 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J-MT and M-CC-H have received research grants from the Michael J. Fox Foundation, the European Commission, France Parkinson, and the Agence Nationale de la Recherche (ANR). J-MT also received funding from the European Regional Development Fund. MM serves as an editorial advisory board member; this role has no bearing on the editorial consideration of this manuscript. SVW is associated with ions.bio. OK is currently affiliated with Genentech. The remaining authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Disclosure and competing interests statement"}}]}}