Leucine-rich repeat kinase 2 (LRRK2) and Parkinson's disease: from genetics to pathobiology

Abstract Point mutations in the leucine-rich repeat kinase 2 (LRRK2) gene cause autosomal-dominant inherited Parkinson's disease (PD), and more common variations increase lifetime risk for PD. LRRK2 encodes a multidomain enzyme with kinase and GTPase activities. Because the hyperactive G2019S mutation in the kinase domain represents a common genetic cause of PD, LRRK2 is currently the most attractive pharmacological target in PD owing to its “druggable” nature, with more than 100 inhibitors developed to date. However, if LRRK2 inhibitors have entered phase I clinical trials, the current understanding of LRRK2 function and dysfunction in neuronal and nonneuronal cells is still primitive. This chapter offers a comprehensive overview of LRRK2 genetics, biochemistry, and biology, as well as a therapeutic perspective of targeting LRRK2 as a disease-modifying therapy in PD.