Urinary proteome profiling in rats and humans unveils biomarkers of LRRK2 kinase activity in Parkinson's disease

ABSTRACT: Pathogenic mutations in Leucine-rich repeat kinase 2 (LRRK2) are the predominant genetic cause of Parkinson's disease (PD) and often lead to increased kinase activity, making LRRK2 inhibitors promising treatment options. However, despite ongoing clinical trials, specific, sensitive, and non-invasive biomarkers for measuring drug target engagement or stratifying mutation carriers remain elusive. Analyzing urinary proteome profiles of 1,214 individuals with PD and/or LRRK2 mutations across three cohorts, we identified 177 significantly altered urinary proteins linked to dysregulation of immune system processes, membrane trafficking and lysosomal-glycosphingolipid metabolism in pathogenic LRRK2 carriers. Machine learning narrowed these features down to a cohort-agnostic panel of 30 key urinary proteins -primarily associated with lysosomal dysfunction- that serve as a robust readout of LRRK2 activity. Our model excelled in classifying mutation status, achieving a ROC AUC of 91%, 84% sensitivity, and 85% specificity. Additionally, urinary proteome profiling of knockout and G2019S Lrrk2 rats, along with those treated with two potent LRRK2 inhibitors, validated the utility of this urinary protein panel for assessing the pharmacodynamic response to LRRK2 inhibitors in clinic. Together, our urinary biomarker candidates for assessing LRRK2 hyperactivation and inhibition will be vital for supporting current and future therapeutic strategies focused on restoring LRRK2's normal physiological function in PD.

INSTRUMENT(S):

ORGANISM(S): Rattus Norvegicus (rat)

TISSUE(S): Urine, Brain, Lung, Kidney

DISEASE(S): Parkinson's Disease

SUBMITTER: Mario Oroshi  

LAB HEAD: Matthias Mann

PROVIDER: PXD057308 | Pride | 2026-01-21

REPOSITORIES: Pride