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Researchers report a critical role for the complement system in early macular degeneration
Date:8/15/2013

lar degeneration. Basal deposits are precursors of drusen, which appear as spots in the retina on clinical examination, and are accumulations of proteins and lipids outside the retinal cells; their presence is the first clinical indication of a risk of developing macular degeneration.

The findings are important because they suggest that inherited macular degenerations share common features with AMD, such as a complement-mediated response to abnormal extracellular matrix. The results also suggest that alterations in the activity of the complement system are involved in the earliest stages of disease pathogenesis. This finding has important implications for the use of drugs that modulate the complement system for treating macular degenerations.

For these studies, the investigators used a mouse model of the inherited macular dystrophy Doyne Honeycomb Retinal Dystrophy/Malattia Leventinese (DHRD/ML) which is caused by the p.Arg345Trp mutation in the EFEMP1 gene. This mutation leads to extensive drusen in patients with DHRD/ML, and the gene targeted Efemp1R345W/R345W mice develop extensive basal deposits.

As a first step in their studies, Dr. Garland and colleagues used proteomic techniques to identify the proteins present in the basal deposits of the Efemp1R345W/R345W mice. Like they do in people, these deposits form between the retinal pigment epithelial cells and their basement membrane, which is called Bruch's membrane and is composed of extracellular matrix. These studies showed that the basal deposits are composed of normal extracellular matrix components that are present in abnormal amounts. This is logical because the EFEMP1 protein is secreted by retinal cells and is thought to be required for maturation of elastin fibers, which are part of Bruch's membrane.

The proteomic analyses also suggest that the altered extracellular matrix stimulates a local immune response, including activation of the complement system. The com
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Contact: Mary Leach
Mary_Leach@meei.harvard.edu
Massachusetts Eye and Ear Infirmary
Source:Eurekalert

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