The Role of A2E in RPE Atrophy

Janet Sparrow, PhD
Trustees of Columbia University (New York, NY)
Year Awarded:
2003
Grant Duration:
April 1, 2003 to March 31, 2005
Disease:
Macular Degeneration
Award Amount:
$150,000
Grant Reference ID:
M2003043
Award Type:
Standard
Award Region:
US Northeastern

The Role of A2E in RPE Atrophy

Details


It has long being suspected that macular pigments composed of the carotenoids lutein and zeaxanthin protect the retina both by filtering high energy blue light and by serving an antioxidant function, but the specific photochemical reactions that these nutrients protect against remain unknown. Dr. Sparrow has proposed that the lutein and zeaxanthin in retinal pigment epithelium (RPE) cells protect against the light-induced oxidative changes (photoxidation) of an aging fluorescent compound (A2E), which accumulates in these cells. She has also hypothesized that lutein and zeaxanthin suppress similar photooxidative changes in the A2E precursor molecule, called A2-PE. In earlier work, she demonstrated that the excitation of A2E with blue light leads to the generation of singlet oxygen and that these reactive oxygens are subsequently inserted into the A2E molecule (photooxidation) creating a very reactive derivative with the potential for damaging cellular macromolecules such as protein and DNA. Her goal now is to demonstrate that the precursor A2-PE undergoes the same photooxidative change, and to determine whether lutein and zeaxanthin protect against the photooxidation of A2E and A2-PE. Then her team will test the assumption that these carotenoids prevent photoxidative changes in A2E and A2-PE through their ability to deactivate the highly reactive oxygen species (singlet oxygen). They will compare lutein and zeaxanthin's antioxidant capabilities and determine whether these nutrients can act in synergy with vitamin E and vitamin C, other natural antioxidants that are present in these cells. The long-term goal of this work is to develop therapies that would counteract the photochemical events initiated by A2E. This project is a continuation of an MDR-funded study began in 2001.

Publications

Sparrow JR, Zhou J, Cai B. 2003. DNA is the target of the photodynamic effects elicited in A2E-laden RPE by blue light illumination. Invest Ophthalmol Vis Sci 44:2245-2251.  

Kim SR, Fishkin N, Kong J, Nakanishi K, Allikmets R, Sparrow JR. 2004. The Rpe65 Leu450Met variant is associated with reduced levels of the RPE lipofuscin fluorophores A2E and iso-A2E. Proc Natl Acad Sci 101:11668-11672.  

Kim SR, Nakanishi K, Itagaki Y, Sparrow JR. 2006. Photooxidation of A2-PE, a photoreceptor outer segment fluorophores and protection by lutein and zeaxanthin. Exp Eye Research 82: 828-839.  

Sparrow JR, Fishkin N, Zhou J, Cai B, Jang YP, Krane S, Itagaki Y, Nakanishi K. 2003. A2E, a byproduct of the visual cycle. Vision Research 43: 2983-2990.  

Sparrow JR, Cai B, Fishkin N, Jang YP, Krane S, Vollmer HR, Zhou J, Nakanishi K. 2003. A2E, a fluorophore of RPE lipofuscin: Can it cause RPE degeneration? Adv Exp Med and Biol. 533:205-211.  

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