Leucine-rich repeat kinase 2 is involved in the microtubule-mediated regulation of intraocular pressure.

Leucine-rich repeat kinase 2 (LRRK2) is known as the most common gene responsible for familial Parkinson disease (PD). This protein plays a key role in the neurodegenerative pathways associated with PD. LRRK2 also plays critical roles in actin dynamics and microtubule cytoskeletal assembly in the cells. In addition to PD, actin and microtubule cytoskeletons are associated with the onset and development of glaucoma by regulating the intraocular pressure (IOP) in humans and animals. However, the role of LRRK2 in regulating IOP remains unclear. Hence, this study investigated the contribution of LRRK2 to cytoskeleton-mediated regulation of IOP. LRRK2 was detected in primary human trabecular meshwork cells by immunofluorescence and western blotting analysis. Inhibition of the function and the expression of LRRK2 by LRRK2 inhibitors and LRRK2 siRNA, induced a significant reduction of TEER in these cells. TEER reduction by an LRRK2 inhibitor was attenuated by paclitaxel, a-tubulin polymerization inducer, but not by jasplakinolide, an actin polymerization inducer, suggesting that inhibition of LRRK2 induced depolymerization of microtubules, resulting in decreased TEER. Finally, LRRK2 gene knockout and LRRK2 inhibition led to a significant reduction of IOP in C57BL6J mice and Japanese white rabbits, respectively. These results suggested that LRRK2 is associated with catalysis of a-tubulin in trabecular meshwork cells and regulates IOP in mice and rabbits. Hence, there is a possibility that an LRRK2 inhibitor contributes to glaucoma therapeutics. Further evaluation to clarify the role of LRRK2 in IOP regulation is needed. SIGNIFICANCE STATEMENT: In this study, a significant contribution of LRRK2 to the regulation of intraocular pressure (IOP) was shown. Inhibition of LRRK2 results in a decrease in TEER of the trabecular meshwork cells, associated with the depolymerization of microtubules. Furthermore, both LRRK2 knockout and administration of the LRRK2 inhibitor induced a significant decrease in the IOP in animals. These results clearly indicate the role of LRRK2 in the regulation of IOP and the possibility of a novel therapeutic approach to glaucoma.