Targeting leucine-rich repeat kinase 2 in Parkinson's disease

Parkinson's disease (PD), is a common progressive neurodegenerative disorder, and missense mutations in the LRRK2 gene are the most common single genetic cause of autosomal dominant PD and polymorphic variants modulate risk in sporadic PD. Earlier research focused on LRRK2 genetics, but with the recent discoveries of LRRK2 substrates/interactors, LRRK2-specific mechanisms are being unveiled.

As a multi-domain protein, LRRK2 possess diverse functions that range from housekeeping, signaling to clearance of proteins. Proteins that interact with LRRK2 have drawn attention to several pathophysiologic pathways that could potentially be targeted in the development of new therapies. This review will discuss the possible physiological roles of LRRK2 based on recently reported interactors as well as place LRRK2 in the disease context. Current LRRK2 inhibition studies and reports about LRRK2 biomarkers will also be discussed as they are important considerations for LRRK2 translational treatment options.

The discovery of LRRK2 as a pathogenic gene in PD has contributed enormously to our understanding of clinical genetics. One of the challenges is to understand the physiologic role of LRRK2 and its specific function that gets disrupted when it is mutated. In vivo LRRK2 models have provided insights but they do not full recapitulate human PD. The identification of LRRK2 interactors opens the opportunities for identification of new therapeutic targets. Ways of quantification of kinase activity in vivo and determining what constitutes physiologic inhibition will need to be further investigated before specific pharmacologic agents can be meaningfully utilized.