Modeling LRRK2 Pathobiology in Parkinson's Disease: From Yeast to Rodents

Mutations in the leucine-rich repeat kinase 2 (LRRK2, PARK8) gene represent the most common cause of familial Parkinson's disease (PD) with autosomal dominant inheritance, whereas common variation at the LRRK2 genomic locus influences the risk of developing idiopathic PD. LRRK2 is a member of the ROCO protein family and contains multiple domains, including Ras-of-Complex (ROC) GTPase, kinase, and protein-protein interaction domains. In the last decade, the biochemical characterization of LRRK2 and the development of animal model s have provided important insight into the pathobiology of LRRK2. In this review, we comprehensively describe the different models employed to understand LRRK2-associated PD, including yeast, invertebrates, transgenic and viral-based rodents, and patient-derived induced pluripotent stem cells. We discuss how these models have contributed to understanding LRRK2 pathobiology and the advantages and limitations of each model for exploring aspects of LRRK2-associated PD.