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

Duc Tung Vu1, William Sibran2, Andreas Metousis1

  • 1Department of Proteomics and Signal Transduction Max Planck Institute of Biochemistry, Am Klopferspitz 18, 82152, Martinsried, Germany.

Molecular Systems Biology
|January 29, 2026
PubMed

Insights

Researchers identified 30 urinary proteins that can detect Parkinson's disease-linked LRRK2 mutations. These biomarkers, found in urine, show promise for monitoring LRRK2 pathway modulation in clinical trials.

Area of Science:

  • Neuroscience
  • Genetics
  • Biochemistry

Background:

  • Pathogenic mutations in Leucine-rich repeat kinase 2 (LRRK2) are a primary genetic cause of Parkinson's disease (PD).
  • Increased LRRK2 kinase activity is common in PD, making LRRK2 inhibitors a potential therapeutic strategy.
  • Current methods for monitoring LRRK2 pathway modulation are limited and often invasive.

Purpose of the Study:

  • To identify non-invasive biomarkers for LRRK2 pathway modulation in Parkinson's disease.
  • To establish urine proteomics as a tool for assessing LRRK2 dysfunction and treatment response.
  • To nominate candidate pharmacodynamic markers for LRRK2-targeted clinical trials.

Main Methods:

  • Urinary proteome profiling of 1215 individuals across three cohorts, integrated with whole-genome sequencing (>500 participants).
  • Machine learning analysis to identify a minimal panel of proteins associated with pathogenic LRRK2 mutations (G2019S).
  • Multi-organ and urinary proteomics in rat models of LRRK2 gain/loss-of-function and LRRK2 inhibition.

Main Results:

  • Identified 177 urinary proteins linked to pathogenic LRRK2, enriched in lysosomal, immune, and membrane-trafficking pathways.
  • Developed a 30-protein panel that accurately classifies G2019S carriers (AUC 0.91) across cohorts.
  • Demonstrated cross-species overlap in urinary proteins reflecting LRRK2 modulation, with strong kidney responses in rats.
  • Rat model perturbations predicted LRRK2 mutation status in patients (AUC 0.75) and were reversed by LRRK2 inhibition.

Conclusions:

  • Urine is a viable, non-invasive matrix for detecting systemic and brain-relevant consequences of LRRK2 dysfunction.
  • The identified 30-protein panel serves as a promising biomarker for LRRK2 mutation status and pathway modulation.
  • These findings support the use of urinary proteomic markers in LRRK2-directed Parkinson's disease clinical trials.
Keywords:
BiomarkerLRRK2Parkinson’s DiseaseProteomicsUrine

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