Study of the cellular and molecular consequences of LRRK2 kinase inhibition as potential disease-modifying therapeutic target for Parkinson’s disease

Parkinson’s disease (PD) is the most common neurodegenerative motor disease, affecting 6.3 million people worldwide. Given the predicted increase in average population age, the number of PD patients is expected to rise and hence the social and economic burden of the disease will increase. 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 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. We and others have found that LRRK2 kinase inhibition induces not only LRRK2 dephosphorylation but also destabilization and it is unclear whether this is a desired or an unwanted effect regarding therapeutic approaches. In this project we aim to understand the consequences of LRRK2 kinase inhibition at both the molecular and cellular level. The strength and innovative nature of this project lies in linking the molecular and cellular effects of LRRK2 kinase inhibition, which will answer one of the most important outstanding questions namely whether LRRK2 kinase inhibitor-induced dephosphorylation and destabilization is beneficial or rather an unwanted side effect for PD drug discovery.