Leucine-rich repeat kinase 2 promotes disintegration of retinal pigment epithelial cell: Implication in the pathogenesis of dry age-related macular degeneration

Recent epidemiological studies have shown that patients with age-related macular degeneration (AMD) have a considerably higher risk of developing Parkinson's disease (PD) later in life, suggesting a possible link between these diseases. However, the common mechanisms between these two diseases remain obscure, although the pathophysiology of each has been well investigated. In this study, we sought to explore the shared pathological features of AMD and PD by focusing on leucine-rich repeat kinase 2 (LRRK2) and α-synuclein, both of which play crucial roles in PD pathogenesis. Immunohistochemistry for LRRK2 and α-synuclein was performed on human eye specimens. The effect of LRRK2 on retinal pigment epithelium (RPE) cell function was investigated using the RPE cell line hTERT-RPE1. Retinal morphology and function were examined in LRRK2-G2019S transgenic mice, representing mutants with increased kinase activity of LRRK2. Immunohistochemistry revealed that LRRK2 and α-synuclein were present in the RPE layer of the human eye. Overexpression of LRRK2 in RPE cells increased α-synuclein and induced cell death. LRRK2 inhibited α-synuclein degradation via phosphorylation of RAB GTPases. LRRK2-G2019S transgenic mice exhibited apoptosis of RPE and photoreceptors, choroidal thinning, and reduced electroretinogram amplitude, on top of α-synuclein protein accumulation in the RPE cell layer. Taken together, the current study revealed that LRRK2 is one of the key molecules involved in the common pathological mechanisms of AMD and PD.