ABCR, the ATP-binding cassette transporter responsible for Stargardt macular dystrophy, is an efficient target of all-trans-retinal-mediated photooxidative damage in vitro. Implications for retinal disease.
A large body of experimental and clinical data have documented the damaging effects of light exposure on photoreceptor cells although the identities of the biologically relevant molecular targets of photodamage are still uncertain. Several lines of evidence point to retinoids or retinoid derivatives as chromophores that can mediate light damage. We report here that ABCR, a photoreceptor-specific transporter involved in the recycling of all-trans-retinal, is unusually sensitive to photooxidation damage mediated by all-trans-retinal in vitro. Partial loss of ABCR function is responsible for Stargardt macular dystrophy, which is associated with accumulation of A2E, a diretinoid adduct within the retinal pigment epithelium. Photodamage to ABCR causes it to aggregate in SDS gels and results in the loss of retinal-stimulated ATPase activity. Peripherin/RDS and ROM-1, two structural proteins that colocalize with ABCR at the outer segment disc rim, are also significantly more susceptible to all-trans-retinal-mediated photodamage than are the major proteins from the rod outer segment. These observations imply that there may be specific protein targets of photodamage within the outer segment, and they may be especially relevant to assessing the risk of light exposure in those individuals who already have diminished ABCR activity due to mutation in one or both copies of the ABCR gene.
Sun
H
H
Departments of Molecular Biology and Genetics, Neuroscience, and Ophthalmology and the Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Nathans
J
J
D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000818:Animals; D002417:Cattle; D003317:Corneal Dystrophies, Hereditary / Q000378:metabolism*; D018384:Oxidative Stress; D012172:Retinaldehyde / Q000494:pharmacology*; D012374:Rod Cell Outer Segment / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects*; D014466:Ultraviolet Rays
D018528:ATP-Binding Cassette Transporters; D012172:Retinaldehyde