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

ABSTRACT: Pathogenic mutations in LRRK2 are the predominant genetic cause of 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 1,215 individuals across three cohorts and integrating WGS 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 perform

SUBMITTER: Duc Tung Vu 

PROVIDER: S-SCDT-10_1038-S44320-026-00190-0 | biostudies-other |

REPOSITORIES: biostudies-other