Leucine rich repeat kinase 2 (LRRK2) is a major genetic determinant of Parkinson’s disease (PD) involved in intracellular organization and vesicular physiology (including regulation of cytoskeleton, neurotransmission, endolysosomal system among others). Work by us and others show that LRRK2 works as a signaling molecule and the LRRK2 pathway is considered a priority area to develop novel therapeutic targeting approaches and biomarkers for PD. Our primary focuses are the study of LRRK2 signaling partners that affect LRRK2 activity (LRRK2 modifiers) as well as the study of signatures of LRRK2 activity. A central phenomenon of our study of LRRK2 is its phosphorylation, which is modified in disease, in particular the study of the interplay between LRRK2 and its phosphoregulating proteins such as the phosphatases PP1 and PP2A or 14-3-3 proteins that bind and protect phosphosites.

A major overall goal of our work is to develop strategies to disrupt LRRK2 complexes with its phosphoregulating partners as a therapeutic approach. Using structural, biophysical and biochemical approaches, we delimit binding interfaces between LRRK2 and its partners and protein-protein interaction modulators (PPIM) for the LRRK2:phosphatases complexes. Using cellular and in vivo methods, we then characterize how LRRK2 phosphorylation is affected by its phosphoregulation complex and validate PPIMs. For the most promising PPIMs, we proceed with validating their effect in cellular and in vivo models of disease. This approach is pursued in parallel with work (often done in collaboration) to develop and test agents that can modulate LRRK2 complexes as potential therapeutics.

A corollary of our hypothesis that the LRRK2 pathway is disturbed in disease is that LRRK2 related biomarker signatures would be altered in PD patients as well as in disease models. Therefore, a complementary aspect of our work is to study LRRK2 signatures, including LRRK2 pathway markers such as pS910/pS935-LRRK2, pS1292-LRRK2 or phosphorylation of Rab substrates, as well as omics signatures in patient cohorts and animal models. Recently, we found that S910 and S935 phosphorylation is reduced in urinary exosomes of PD patients (Taymans et al. NPJ PD 2023) and we also collaboratively determined proteomics signatures of LRRK2 activation in urine of LRRK2 PD patients as well as LRRK2 rat models (Vu et al. 2026).