Information from the National Eye Institute
A protein that normally deposits mineralized calcium in tooth enamel may also be responsible for calcium deposits in the back of the eye in people with dry age-related macular degeneration (AMD), according to a study from researchers at the National Eye Institute (NEI). This protein, amelotin, may turn out to be a therapeutic target for the blinding disease. The findings were published in the journal Translational Research. NEI is part of the National Institutes of Health.
“Using a simple cell culture model of retinal pigment epithelial cells, we were able to show that amelotin gets turned on by a certain kind of stress and causes formation of a particular kind of calcium deposit also seen in bones and teeth. When we looked in human donor eyes with dry AMD, we saw the same thing,” said Graeme Wistow, Ph.D., chief of the NEI Section on Molecular Structure and Functional Genomics, and senior author of the study.
Recently, researchers found a calcium-containing mineral compound called hydroxyapatite (HAP) in dry AMD drusen-like deposits. HAP is a key component of tooth enamel and bone. Small balls of HAP filled with cholesterol, called spherules, were found in drusen only from people with dry AMD, and not in those with wet AMD or without AMD. Wistow’s team discovered that if they starved RPE cells, the cells began to deposit HAP. They determined that the protein amelotin, encoded by the gene AMTN, is strongly activated after extended starvation and is responsible for the mineralization of HAP. Blocking the genetic pathway in their RPE cell line blocked the production of these deposits.
Why RPE cells in dry AMD begin depositing these HAP spherules is unclear, but Wistow thinks it may be a protective mechanism gone awry. It’s possible, he says, that these protein, lipid, and mineral deposits may help damaged RPE cells block blood vessels from growing into the retina, a problem that is one of the key features of wet AMD. But when the mineral deposits get too extensive, they may also block nutrient flow to the RPE and photoreceptors, leading to retinal cell death.
“Mechanistically, amelotin looks like a key player for the formation of these very specific hydroxyapatite spherules. That’s what it does in the teeth, and here it is in the back of the eye. Conceptually, you could see coming up with drugs that specifically block the function of amelotin in eye, and this might delay the progression of the disease. But we won’t know until we try it,” said Wistow.
Rajapakse D, Peterson K, Mishra S, Fan J, Lerner J, Campos M, and Wistow G. “Amelotin is expressed in retinal pigment epithelium and localizes to hydroxyapatite deposits in dry age-related macular degeneration.” Translational Research. 2020. doi: 10.1016/j.trsl.2020.02.007