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Faulty Molecules Switches & Certain Genomic Regions Contribute to AMD

Posted by Ilena Di Toro | Posted on June 18, 2019

It is safe to say that no one wants to be blind. While age related macular degeneration (AMD) isn’t as well-known as glaucoma and cataracts, it, too, is a form a blindness that no one wants. It affects the straight on vision that is needed for activities like reading and driving and while medication can help slow the progression of the disease, there is no cure.

Current research is looking into the molecular and genetic factors that lead to AMD. One such research project at the National Eye Institute (NEI) found that a signaling pathway could be involved in the progression of AMD. Scientists knew that certain variations in the genes of the transforming growth factor beta (TGF-beta) may lead to AMD, so that meant that it plays a role in the disease progression. Neurons in a healthy retina emit many signaling molecules, one of which is the TGF-beta. These signals either alert that all is well or that there is a problem. When things are normal, the immune cells, known as microglia, form a branch shape to maintain the health of the neighboring neurons. When the signals change, the microglia either move to injury sites or remove damaged or dead cells.

Since communications between the microglia and neurons are going on all the time, researchers wanted to know if there was a connection between TGF-beta and abnormal microglia, which is found in AMD. To learn more, researchers created genetically modified mice where they could “turn off” the microglia’s ability to sense TGF-beta. When the cells couldn’t sense TGF-beta, they changed shape, went to the wrong locations and started to spread. The microglia also decreased expression of the proteins that help them to sense their environment. The decreased TGF-beta activity switches the microglia to a pro-inflammatory mode, which damages the retina and leads to AMD.

Researchers feel that small changes in the TGF-beta signal are disrupting the operating system in the retina, so the molecule may be a therapeutic target for treating AMD.

Of course, it isn’t just the molecules that can cause trouble, the genes can be troublesome, as well. Another study at NEI located specific genetic targets and their role in AMD. Researchers looked at both the sequences within the DNA that turn the genes on, known as promoters, and the enhancers, which increase the activity of the promoters. They wanted to know if variants regulated gene expression, what were the genes that the variants were regulating.

Over 400 retinas from dead human donors with and without AMD were studied. Part of the study involved sequencing each retinas RNA, the molecule that carries instructions from the DNA for the making of proteins. Over 13,000 protein coding and over 1000 non-protein coding RNA sequences were identified.

Researchers were able to find patterns between the gene expressed in the retina and a pool of over 9 million previously identified genetic variants. This analysis pointed to the disease gene in 6 out of 34 AMD regions. What made this study unique is that it used RNA data to learn more about the genetic make-up of AMD. This study also led to the development of a database of retinal gene expression known as EyeGEx ( This database provides a resource for researchers to study the genetic causes of AMD and other diseases, such as glaucoma and diabetic retinopathy.

While treatment for AMD based on the research of the molecules and genes referenced above are many years away, they both show promise as pathways for treatment.


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