Roc, the G-domain of the Parkinson's disease-associated protein LRRK2

Abstract

Mutation in LRRK2 (Leucine-rich repeat kinase 2) is a common cause of Parkinson’s disease. Aberrant LRRK2 kinase activity is associated with disease pathogenesis, and thus it is an attractive drug target for combating PD. Intense efforts in the past nearly two decades have focused on developing small-molecule inhibitors of the kinase domain of LRRK2, which have identified potent kinase inhibitors. However, most LRRK2 kinase inhibitors have shown adverse effects; therefore, alternative mechanism-based strategies are desperately needed. In this review, we will discuss the new insights gleaned from recent cryo-EM structures of LRRK2 towards understanding the mechanisms of actions of LRRK2 and explore the potential new therapeutic avenues.