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<p>Pathogenic mutations in Leucine-rich repeat kinase 2 (<i>LRRK2</i>) are the predominant genetic cause of Parkinson’s disease (PD) and often increase kinase activity, making LRRK2 inhibitors promising treatment options. 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–proteome 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-<i>LRRK2</i><sup>G2019S</sup> and <i>Lrrk2</i><sup>KO</sup>) and after Lrrk2 inhibition (MLi-2 and PF-475), revealing tissue-specific responses—strongest in kidney—and cross-species overlap, including 24 brain proteins detectable in human urine. Rat-derived perturbations predicted <i>LRRK2</i> 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.</p>

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Multi-cohort, cross-species urinary proteomics reveals signatures of LRRK2 dysfunction in Parkinson’s disease

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月29日

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  • Duc Tung Vu,
  • William Sibran,
  • Andreas Metousis,
  • Laurine Vandewynckel,
  • Basak Eraslan,
  • Liesel Goveas,
  • Ericka CM Itang,
  • Claire Deldycke,
  • Adriana Figueroa-Garcia,
  • Réginald Lefèbvre,
  • Johannes Bruno Müller-Reif,
  • Sebastian Virreira Winter,
  • Marie-Christine Chartier-Harlin,
  • Jean-Marc Taymans,
  • Matthias Mann,
  • Ozge Karayel

摘要

Pathogenic mutations in Leucine-rich repeat kinase 2 (LRRK2) are the predominant genetic cause of Parkinson’s disease (PD) and often increase kinase activity, making LRRK2 inhibitors promising treatment options. 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 >500 participants to map genotype–proteome 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-LRRK2G2019S and Lrrk2KO) and after Lrrk2 inhibition (MLi-2 and PF-475), revealing tissue-specific responses—strongest in kidney—and cross-species overlap, including 24 brain proteins detectable in human urine. Rat-derived perturbations predicted LRRK2 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.