BBSRC-funded researchers at University College London say they have gleaned a key insight into the molecular beginnings of age-related macular degeneration, the number one cause of vision loss in the elderly, by determining how two key proteins interact to naturally prevent the onset of the condition.
In a paper to be published in a forthcoming issue of the Journal of Biological Chemistry, a publication of The American Society of Biochemistry and Molecular Biology (ASBMB), the team reports for the first time how a common blood protein linked to the eye condition reins in another protein that, when produced in vastly increased amounts in the presence of inflammation or infection, can damage the eye.
By starting to understand these interactions in greater detail, we can begin to devise methods that will ultimately prevent the development of blindness in the elderly,” said Zuby Okemefuna, the lead author of the paper to be published January 8.
Age-related macular degeneration, or AMD, is painless but affects the macula, the part of the retina that allows one to see fine detail. One form of the debilitating condition, known as “wet” AMD, occurs when abnormal and fragile blood vessels grow under the macula, leaking blood and fluid and displacing and damaging the macula itself. The second form, “dry” AMD, occurs when light-sensitive cells in the macula slowly break down.
It is believed that both forms start on a common molecular route and then deviate into dry or wet AMD, explained the research leader, Steve Perkins.
The earliest hallmark of AMD is the appearance of protein, lipid and zinc deposits under the retinal pigment epithelial cells,” he said, adding that the yellowish deposits, usually discovered by an ophthalmologist, are commonly known as “drusen.”
The researchers studied two proteins involved in drusen formation – blood protein Factor H and a second blood protein known as C-reactive protein – and showed that Factor H binds to C-reactive protein when C-reactive protein is present in large amounts, as in the case of infection, to reduce the potentially damaging effects of an overactive immune system.
In the eye, during the normal processes of aging, cells will die naturally for all sorts of reasons,” Okemefuna said. “The blood supply to the eye will bring C-reactive protein with it, and a low level of C-reactive protein activity will enable the normal processes of clearance of dead cells at the retina through mild inflammation. In conditions of high inflammation, the levels of C-reactive protein in the retina will increase dramatically.”
Uncontrolled C-reactive protein activity causes damage to the retina, which is followed by more inflammation and then even more damage to the retina, and so forth.
“It’s the debris of broken up retinal cells, some of which is caused by this cycle, that is deposited as drusen,” Okemefuna said.
The team also found that a genetically different form of Factor H does not bind to the C-reactive protein quite as well as the normal one, making people who carry the modified protein more vulnerable to an immune system attack in the eye and, thus, drusen buildup.
“In normal individuals, further damage to the retina by prolonged exposure to high levels of C-reactive protein is prevented by Factor H. C-reactive protein also prevents Factor H from clumping together and initiating the processes that lead to drusen formation,” Perkins said. “Both these ‘good’ activities of Factor H are much reduced in the genetically different form of Factor H.”
While there is no known cure for AMD, existing therapies aim to treat the symptoms and delay progression.
“It is interesting how the interaction of these two blood proteins protects the eye during crisis,” Perkins said. “The two proteins also can be involved in a rare and often fatal cause of kidney failure in children. We now are better positioned to begin to work out preventative strategies for these diseases.”
Ruodan Nan, Ami Miller and Jayesh Gor also were co-authors on the study, which was funded over the past three years by University College London, the Biotechnology and Biological Sciences Research Council, the Mercer Fund of the Fight for Sight Charity and the Henry Smith Charity.
About the American Society for Biochemistry and Molecular Biology
The ASBMB is a nonprofit scientific and educational organisation with more than 12,000 members worldwide. Most members teach and conduct research at colleges and universities. Others conduct research in various government laboratories, at nonprofit research institutions and in industry. The Society’s student members attend undergraduate or graduate institutions.
For more information about ASBMB, visit www.asbmb.org.
About the University College London
Founded in 1826, UCL was the first English university established after Oxford and Cambridge, the first to admit students regardless of race, class, religion or gender, and the first to provide systematic teaching of law, architecture and medicine. UCL is the fourth-ranked university in the 2009 THES-QS World University Rankings. UCL alumni include Marie Stopes, Jonathan Dimbleby, Lord Woolf, Alexander Graham Bell, and members of the band Coldplay. UCL currently has over 12,000 undergraduate and 8,000 postgraduate students. Its annual income is over £600 million. Website: www.ucl.ac.uk.
The Biotechnology and Biological Sciences Research Council (BBSRC) is the UK funding agency for research in the life sciences. Sponsored by Government, BBSRC annually invests around £450M in a wide range of research that makes a significant contribution to the quality of life for UK citizens and supports a number of important industrial stakeholders including the agriculture, food, chemical, healthcare and pharmaceutical sectors. BBSRC carries out its mission by funding internationally competitive research, providing training in the biosciences, fostering opportunities for knowledge transfer and innovation and promoting interaction with the public and other stakeholders on issues of scientific interest in universities, centres and institutes.
The Babraham Institute, Institute for Animal Health, Institute of Food Research, John Innes Centre and Rothamsted Research are Institutes of BBSRC. The Institutes conduct long-term, mission-oriented research using specialist facilities. They have strong interactions with industry, Government departments and other end-users of their research.
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