Tooth-enamel Proteins Were Discovered in Eyes with Dry AMD

According to the findings of a study from researchers at the National Eye Institute, a protein called amelotin that normally deposits mineralized calcium in tooth enamel may also play role for calcium deposits in the back of the eye in people with dry age-related macular degeneration (AMD). This protein, according to the researchers, may turn out to be a therapeutic target for the binding disease.

"Using a simple cell culture model of retinal pigment epithelial cells, we were able to show that amelotin turns on under some stress and leads to some calcium deposition also seen in bones and teeth. Human donors can see the same results in dry AMD eyes, said Dr. Graeme Wistow, head of the NEI Section on Molecular Structure and Functional Genomics and senior author of the study.

AMD comes in two forms – wet and dry. Although there are therapies that can slow the progression of wet AMD, there is currently no therapy for dry AMD (also known as geographic atrophy). In dry AMD, deposits of cholesterol, lipid, protein, and minerals accumulate in the back of the eye. Some of these deposits are called molluscum and differ in composition from those found in wet AMD. Drusen form beneath the retinal pigment epithelium (RPE) and a layer of cells transports nutrients from the underlying blood vessels to support photoreceptor cells in the superior retina. As drusen develop, RPE and eventually photoreceptor cells die, leading to blindness. The photoreceptor cannot regrow, so blindness is permanent.

Recently, researchers have discovered a calcium-containing mineral compound called hydroxyapatite (HAP) in dry AMD deposits. HAP is a key component of enamel and bone. Cholesterol-filled HAP globules were found only in drusen of dry AMD patients, but not in wet AMD or people without AMD.

In this study, Wistow's team found that if RPE cells grown in trans-pores (a cell culture system) starved for 9 days, the cells began to deposit HAP. They determined that amelotin, a protein encoded by the AMTN gene, is strongly upregulated after prolonged starvation and leads to HAP mineralization in their cell culture model. Blocking this pathway in their RPE cell line also blocked the production of these drusen deposits.

To verify that their cell culture model could accurately represent dry AMD, the researchers examined human cadavers with dry AMD, wet AMD, or without AMD. They found HAP and amelotin only in dry AMD eyes, but not in the other eye. Although amilostine was sometimes found in dry AMD areas without drusen, it was mainly present in areas with numerous HAP deposits.

"No one really knew how hydroxyapatite accumulated in dry AMD drusen before this study was conducted," said the first author of the study—r. Dinusha Rajapakse. "It was indeed unexpected to find this tooth-specific protein in the eye, a protein related to hydroxyapatite deposition."

Why RPE cells in dry AMD begin to deposit these HAP spheres is unknown, but Wistow suggests that this may be a failure of protective mechanisms. These protein, lipid and mineral deposits may help damaged RPE cells prevent blood vessel growth into the retina, one of the key features of wet AMD, he said. But when mineral deposits become too much, they may also prevent the flow of nutrients to the RPE and photoreceptor cells, thus leading to retinal cell death.

"Mechanistically, amelotin looks like a key factor in the formation of these very special hydroxyapatite pellets. This is what it does in the teeth, and in the back of the eye. Conceptually, you will see the emergence of Wistow, a drug that specifically blocks drugs, saying: "Aloretin functions in the eye and may delay the progression of the disease. But, we don't know until we try it."

Good animal models for testing dry AMD therapies are urgently needed. Based on the findings of this study, Wistow and his team are creating new mouse models for this disease. In addition, Wistow suggested that his cell culture model mimicking the characteristics of dry AMD may be useful for high-throughput drug screening to discover molecules that slow or prevent the development of soft drusen.

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