The Eyes Have It
Authors: Seydel Caroline 
Published: August 2003

When junk builds up between the retina and its neighboring layer, blindness often follows. To find a way to preserve sight, researchers have now sifted through the deposits, called drusen, looking for clues to their origin. The results provide the first molecular evidence that oxidative damage fuels drusen formation and contributes to age-related blindness.

The leading cause of blindness among the elderly in developed countries, age-related macular degeneration (AMD) afflicts 25 million people worldwide. AMD destroys a central area of the retina called the macula, which provides high-resolution vision. As cells in the macula break down, drusen accumulate and vision blurs. No one knows how drusen form or even whether they cause AMD (see
"Eyes on Epo"
). Although AMD has a genetic component, scientists have not found a single gene that underlies a significant proportion of cases. In hopes of uncovering a "smoking gun" protein that would provide a chink in AMD's armor, Crabb and colleagues developed a way to isolate drusen and analyze their makeup.

The researchers culled drusen from 18 normal and five diseased eyes obtained from tissue banks and identified 129 different proteins, some of which were potentially unique to AMD-stricken eyes. None implicated an obvious mechanism for drusen formation. But when the researchers looked more closely at proteins from AMD-associated drusen, they found that several contained lipid fragments that were generated by oxidation. These observations raise the possibility that such chemical modifications contribute more to drusen formation than does a single "disease protein" and that oxidative damage could trigger the disease.

Researchers disagree about oxidation's role in AMD. Previous studies have uncovered immune system proteins in drusen, and the current work confirms those observations. Some investigators propose that blood-borne molecules of the immune system collect to form drusen. Others suspect that oxidative stress in the eye stimulates the immune response. Light bombards the retina, and the blood flowing through it teems with oxygen, providing ample opportunity for oxidation. Furthermore, antioxidants sometimes hinder the disease, and smoking, which causes oxidative damage in many tissues, increases risk of AMD. Such studies provide only indirect evidence that oxidation causes AMD, however. The current work establishes that oxidized products collect in drusen. In addition, the fatty acid that spawned the lipid fragments is most abundant in the retina, which supports the notion that the deposits originate locally, the researchers say. Crabb and colleagues hypothesize that oxidative damage splinters fatty acids and cross-links the pieces to proteins outside cells. The cross-linked molecules attract immune system proteins, which add to the debris.

"It's the first analysis of its kind on drusen," says cell biologist Dean Bok of the University of California, Los Angeles. This study dissected drusen protein by protein rather than searching for one specific protein. The small number of AMD-afflicted eyes examined, however, limits the strength of the findings, and questions remain about exactly where the oxidized molecules originate. Still, showing that such molecules contribute to drusen gives the stress model a firm footing, he says, and it might help AMD researchers see things more clearly.

--Caroline Seydel

J. W. Crabb, M. Miyagi, X. Gu, K. Shadrach, K. A. West, H. Sakaguchi, M. Kamei, A. Hasan, L. Yan, M. E. Rayborn, R. G. Salomon, J. G. Hollyfield, Drusen proteome analysis: An approach to the etiology of age-related macular degeneration.
Proc. Natl. Acad. Sci. U.S.A.
, 21 October 2002 [e-pub ahead of print].
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