Mechanism Of All-Trans-retinal Toxicity: Implications For Stargardt’S Disease And Age-related Macular Degeneration

Abstract

Purpose: : Compromised clearance of all-trans-retinal (atRAL), a component of the retinoid cycle, increases the susceptibility of mouse retina to acute light-induced photoreceptor degeneration. Abca4^_/_Rdh8^_/_ mice featuring defective atRAL clearance were used to examine the underlying molecular mechanism(s) because bright light exposure causes severe photoreceptor degeneration in these animals.

Methods: : Various pharmacological agents were tested and evaluated using morphological, biochemical and functional approaches in Abca4^_/_Rdh8^_/_ mouse model.

Results: : Bright light exposure of Abca4^-/-Rdh8^-/- mice increased atRAL levels in the retina that induced rapid NADPH oxidase-mediated overproduction of intracellular reactive oxygen species (ROS). Moreover, such ROS generation was inhibited by blocking phospholipase C and IP₃-induced Ca²⁺ release, indicating that activation occurs upstream of NADPH oxidase-mediated ROS generation. Because multiple upstream G protein-coupled receptors (GPCRs) can activate phospholipase C, we then tested the effects of antagonists of serotonin 2A (5-HT_2AR) and M₃-muscarinic (M₃R) receptors and found they both protected Abca4^-/-Rdh8^-/- mouse retinas from light-induced degeneration.

Conclusions: : A cascade of signaling events appears to mediate the toxicity of atRAL in light-induced photoreceptor degeneration of Abca4^-/-Rdh8^-/- mice. A similar mechanism may be operative in human Stargardt’s disease and age-related macular degeneration.

Keywords: age-related macular degeneration • retinal degenerations: cell biology • photoreceptors