HTRA1-dependent proteolysis induces age-related retinal degeneration and exacerbates choroidal neovascularization

Polymorphisms in the ARMS2/HTRA1 locus on chromosome 10 enhance the risk of geographic atrophy and macular neovascularization, the advanced forms of age-related macular degeneration (AMD). Although HTRA1 mutations have been associated with microvascular defects in the brain, it remains unclear whether changes in HTRA1 expression contribute to AMD pathophysiology. In this study, we showed that, in AMD donor eyes, HTRA1 protein accumulated around the retinal pigment epithelium (RPE)/photoreceptor lesions. We then demonstrated that overexpression of catalytically active, but not catalytically inactive, HTRA1 in RPE cells in mice induced age-dependent loss of photoreceptors, inflammation and a decline in photoreceptor functional responses. This retinal degeneration was not exacerbated when the mice were exposed to phototoxic stress in the constant light exposure preclinical model. However, mice overexpressing catalytically active HTRA1 had significant exacerbation of laser-induced choroidal neovascularization lesions. Finally, as substrate processing may define the molecular basis for HTRA1-induced retinal degeneration, we initiated a proteomics approach and identified the visual cycle key player RBP3 as a disease-relevant HTRA1 substrate in the retina.