Integrated Biofluid Proteomics Identified Dynamic Functional Biomarkers of LRRK2-Linked Parkinson's Disease Progression

Leucine-rich repeat kinase 2 (LRRK2) variants are the most common cause of inherited Parkinsons disease (PD), and the hyperactivity of the LRRK2 variants represent a validated drug target for PD. The penetration of common LRRK2 variants is incomplete, underscoring the need for molecular biomarkers that predict disease onset and guide therapeutics development. Here, we analyzed large datasets of cerebrospinal fluid (CSF) and urinary proteomics from the Parkinsons Progression Markers Initiative (PPMI) and identified distinct lysosomal and immune protein signatures as potential biomarkers for LRRK2-linked PD (LRRK2 PD). Longitudinal analysis revealed that levels of specific lysosomal and immune proteins remained elevated in CSF during the prodromal phase but declined following clinical symptom onset. Furthermore, examination of multiple brain cell types from Lrrk2 mutant mice carrying disease variant (G2019S) showed heightened secretion of lysosomal proteins in microglia and astrocytes, but not neurons, supporting a glial origin and intrinsic LRRK2 mutant activity responsible for the elevated CSF lysosomal proteins. Furthermore, proteomics analysis of urine from humanized LRRK2G2019Stransgenic mice identified lysosome and glycosphingolipid protein signatures shared with human LRRK2 PD patients. Collectively, our integrated proteomics reveals dynamic changes of functional biofluid signatures for LRRK2 PD, which enables the determination of biomarkers for early disease onset. The humanized LRRK2G2019S mice provide a valuable platform for biomarker refinement and therapeutic development. One Sentence SummaryIntegrated human and mouse proteomic analyses identify dynamic lysosomal and immune biofluid signatures, possibly of glial origin, as functional biomarkers of LRRK2-linked Parkinsons disease progression, supported by a novel humanized LRRK2G2019S mouse model that recapitulates key urinary biomarker profiles.