LRRK2-directed therapeutics in Parkinson's disease: from molecular tools to functional insights

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by motor impairment and the build-up of protein aggregates. Current therapies aim to manage the symptoms, but there is no known cure for Parkinson’s disease. Genetic research has identified Leucine-Rich Repeat Kinase 2 (LRRK2) as a key factor in familial and sporadic PD cases.  Since the LRRK2 kinase activity is increased in PD, many ATP-competitive kinase inhibitors that specifically target LRRK2's kinase activity have been developed, but these often come with serious side effects, particularly affecting the lungs and kidneys in animal studies. Therefore, this thesis explores novel methods and tools for studying and therapeutically targeting LRRK2 through various biochemical and cellular techniques. 

Recent research on LRRK2 in immune cells led us to establish THP-1 monocytes as a new human cell model. Our findings confirm LRRK2's role in immune responses, particularly phagocytosis (uptake). In most of our cells, LRRK2 usually exists as a single unit, or monomer, and becomes active when it dimerizes (consisting of 2 units) and moves to the cell membrane, therefore having a monomer-dimer cycle. We introduced a novel method, Brightness and Diffusion Global Analysis (BDGA), to assess LRRK2 dimerization in living cells, revealing insights into its monomer-dimer equilibrium. Subsequently, we designed constrained peptides targeting the COR domain of LRRK2 to prevent dimerization, which reduced kinase activity and protected neuronal cells from apoptosis without mislocalizing LRRK2. This thesis highlights diverse methods to target LRRK2 and offers insights for potential therapies, laying the groundwork for further research and targeted treatments for Parkinson's disease.

Dissertation: https://hdl.handle.net/11370/ab98a497-1aac-4499-8601-3c7d9410e410