LRRK2 and Parkinson Disease

Objectives: To review the molecular genetics and functional biology of leucine-rich repeat kinase 2 (LRRK2) in parkinsonism and to summarize the opportunities and challenges to develop interventions for Parkinson disease (PD) based on this genetic insight.

Data Sources: Publications cited are focused on LRRK2 biology between 2004 and March 2009.

Study Selection: Literature selected was based on original contributions, seminal observations, and thoughtful reviews.

Data Extraction: Unless stated otherwise, data was primarily abstracted from peer-reviewed literature appearing on PubMed.

Data Synthesis: Genetic mutations that predispose PD are diagnostically useful in early or atypical presentations. The molecular pathways identified suggest therapeutic interventions for Lrrk2 and idiopathic PD and the rationale and opportunity to develop physiologically relevant biomarkers and experimental models with which to test them.

Conclusions: Both affected and asymptomatic LRRK2 carriers now provide the opportunity to define the natural history of PD. This includes the frequency, penetrance, and rate of motor symptoms, nonmotor comorbidities, and their associated biomarkers.