Insights into the Molecular Properties of ABCA4 and Its Role in the Visual Cycle and Stargardt Disease

In the membranes of outer photoreceptor segments, nonenzymatically formed toxic bisretinoids are converted upon phagocytosis in the acidic environment of RPE phagolysosomes to bisretinoid pyridinium compound A2E and related bisretinoids.

“In the membranes of outer photoreceptor segments are nonenzymatically formed toxic bisretinoids. Upon phagocytosis, these bisretinoids are in the acidic environment of RPE phagolysosomes converted to bisretinoid pyridinium compound A2E and related bisretinoids [54,69,70,71,72,73,74].”

A2E is insoluble, tends to aggregate, and accumulates as lipofuscin deposits in RPE cells, compromising RPE function and leading to cell death.

“The latter are insoluble, have a tendency to aggregate and accumulate as lipofuscin deposits in the RPE cells, compromising RPE function and leading to cell death.”

ABCA4 protein is a 250 kDa flippase that transports all-trans-retinal across the photoreceptor membrane to the cytoplasmic side, making it an important part of the visual cycle and removal of toxic vitamin A products.

“ABCA4 protein is a 250 kDa flippase, which transports all-trans-retinal, across the photoreceptor membrane to the cytoplasmic side, making it an important part of the visual cycle and removal of toxic vitamin A products [71,92].”

Trapped vitamin A derivatives and toxic compounds can react nonenzymatically to form toxic bisretinoids.

“Trapped vitamin A derivatives and toxic compounds can react nonenzymatically, leading to the formation of toxic bisretinoids.”

ABCA4 dysfunction leads to the accumulation of vitamin A derivatives and toxic compounds in photoreceptor outer segments because they cannot be efficiently removed.

“ABCA4 dysfunction leads to the accumulation of vitamin A derivatives and toxic compounds, as they cannot be efficiently removed from the photoreceptor outer segment.”

Upon phagocytosis of outer segments by RPE cells, bisretinal compounds can be hydrolyzed by lysosomal enzymes to the highly toxic metabolite A2E.

“Upon phagocytosis of outer segments by adjacent RPE cells, the bisretinal compounds can be hydrolyzed by lysosomal enzymes to highly toxic metabolite A2E.”