In vitro modeling of leucine-rich repeat kinase 2 G2019S-mediated Parkinson's disease pathology

Leucine-rich repeat kinase 2 (LRRK2) G2019S (glycine to serine) is the most common mutation associated with sporadic and familial Parkinson's disease (PD) with 80% penetrance by age 70. This mutation is found worldwide, with up to 40% of individuals in the North African Arab population carrying the mutation. Induced pluripotent stem cells derived from fibroblasts of patients carrying the LRRK2 G2019S mutation have been a critical source of cells for generating dopaminergic neurons and studying G2019S-related pathology. These studies have elucidated LRRK2-related mechanisms of mitochondrial dysregulation, increased reactive oxygen species, truncated and simplified neurites, and cell death. These phenotypes are thought to result from the G2019S mutation increasing substrate access and therefore increasing the catalytic rate of the serine/threonine kinase. In this article, we critically review the contributions of in vitro modeling to the current knowledge on LRRK2 G2019S. We also analyze the role of patient-derived cell lines for the identification and validation of therapeutic targets, emphasizing their importance as part of a 3R approach to translational research and personalized medicine.