Characterisation of LRRK2 kinase function in a-synuclein-induced neurotoxicity and neuroinflammation.

Parkinson’s disease (PD) is the most common neurodegenerative motor disease, affecting 10 million people worldwide. To date, PD cannot be cured, instead therapy is directed at alleviating symptoms. A major challenge is therefore the development of disease-modifying therapies which halt, or at least slow down, disease progression. Leucine-rich repeat kinase 2 (LRRK2) kinase inhibitors are currently in a preclinical stage and considered as potential disease-modifying drugs. Although several lines of evidence support the beneficial effects of LRRK2 kinase inhibitors, many fundamental questions ought to be answered before clinical applications can be envisaged. One of these questions is ‘what is the role of LRRK2 and the effects of LRRK2 kinase inhibition in the neuroinflammatory environment, present in PD’. Using state-of-the-art techniques, we aim to answer this question, which is now poorly understood, but of major importance given the neuroinflammation observed in the brain of PD patients. Interestingly, recent findings suggest that a-synuclein might possess conformation-specific immunogenic properties attributing to the progression of the disease. In addition, the identification of new potential therapeutic targets and development of new assays, might be of major interest for further drug screening purposes. Therefore, the obtained results will be a crucial step in the development of a safe and effective LRRK2-based PD therapy.