Repressing c-Jun N-terminal kinase signaling mitigates retinal pigment epithelium degeneration in mice with failure to clear all-trans-retinal

Retinal pigment epithelium (RPE) cell apoptosis arising from all- trans -retinal (atRAL) is in close contact with the etiology of dry age-related macular degeneration (AMD) and autosomal recessive Stargardt's disease (STGD1), but its underlying mechanisms remain elusive. In this study, we reported that c-Jun N -terminal kinase (JNK) activation facilitated atRAL-induced apoptosis of RPE cells. Reactive oxygen species production and endoplasmic reticulum stress were identified as two of major upstream events responsible for activating JNK signaling in atRAL-loaded RPE cells. Inhibiting JNK signaling rescued RPE cells from apoptosis induced by atRAL through attenuating caspase-3 activation leading to poly-ADP-ribose polymerase (PARP) cleavage, and DNA damage response . Abca4 −/− Rdh8 −/− mice upon light exposure exhibit rapidly increased accumulation of atRAL in the retina , and display severe RPE degeneration, a primary attribute of dry AMD and STGD1. Reducing JNK signaling by intraperitoneally injected JNK–IN-8 was highly effective in preventing RPE atrophy and apoptosis in light-exposed Abca4 −/− Rdh8 −/− mice. These findings afford a further understanding for contribution of JNK activation by atRAL to retinal damage .