Genetic markers of age-related macular degeneration revealed

Summary: The discovery of new genetic markers associated with age-related macular degeneration may lead to better diagnosis and treatment of the currently incurable vision disease.

A source: Garvan Institute

The discovery of new genetic markers for the disease brings age-related macular degeneration one step closer to better diagnosis and treatment of the incurable eye disease.

Scientists from the Garvan Institute of Medical Research, the University of Melbourne, the Menzies Institute of Medical Research at the University of Tasmania and the Australian Eye Research Center reprogrammed stem cells to create models of diseased eye cells, then analyzed the DNA and RNA. and to determine the genetic signature of proteins.

“We tested how differences in people’s genes affect the cells involved in age-related macular degeneration. At the smallest scale, we have cut down on specific types of cells to pinpoint the genetic markers of this disease,” says co-author Professor Joseph Powell, Director of Cell Sciences at Garvan.

“This is the foundation of precision medicine, where we can look at which therapeutics will be most effective for a person’s genetic disease profile.”

Age-related macular degeneration, or AMD, is a progressive deterioration of the macular layer in the center of the retina and at the back of the eye, leading to possible deterioration or loss of central vision. One in seven Australians over the age of 50 will develop the disease, and about 15 per cent of those over 80 will have vision impairment or blindness.

The underlying causes of the deterioration remain unknown, but genetic and environmental factors appear to contribute. Risk factors include age, family history, and smoking.

The investigation was published today in the Journal Nature Communications.

The researchers took skin samples from 79 participants with and without late-stage AMD, known as geographic atrophy. Their skin cells were reprogrammed into stem cells called induced pluripotent stem cells, which were then guided by molecular signals to become retinal pigment epithelial cells, the cells affected by AMD.

Retinal pigment epithelial cells form the back of the retina and are critical to the health and function of the retina. Their damage is associated with the death of photoreceptors, which are light-sensing neurons in the retina that transmit visual signals to the brain and are responsible for vision loss in AMD.

Analysis of 127,600 cells identified 439 molecular signatures associated with AMD, 43 of which were potentially novel gene variants. The key pathways identified were subsequently tested inside the cells, revealing differences in energy-generating mitochondria between healthy and AMD cells, suggesting mitochondrial proteins as potential targets for preventing or reversing the course of AMD.

Black and white electron microscopic image of retinal pigment epithelial cells. Credit: Dr. Grace Lidgerwood

Furthermore, molecular signatures can now be used to screen treatments using patient-specific cells in a dish.

“Ultimately, we’re interested in matching a patient’s genetic profile to the best drug for that patient. We need to test how they work in disease-specific cells,” says co-leader of the study, Professor Alice Pebay of the University of Melbourne.

Professor Powell and co-lead authors Professor Pebay and Professor Alex Hewitt from the Menzies Institute of Medical Research in Tasmania and the Australian Eye Research Center are part of a long-standing collaboration to investigate the underlying genetic causes of complex human diseases.

“We’re building a research program where we’re interested in exploring stem cells for large-scale disease modeling,” says Professor Hewitt.

In another recent study, scientists discovered genetic markers of glaucoma using retinal and optic nerve stem cell models.

Researchers are also focusing on the genetic causes of Parkinson’s and cardiovascular disease.

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About it Genetics and Vision Research News

Author: Press service
A source: Garvan Institute
The connection: Press service – Garvan Institute
Photo: Photo courtesy of Grace Lidgerwood

Original research: Open access.
“Transcriptomic and Proteomic Retinal Pigment Epithelial Signatures of Age-Related Macular Degeneration” Joseph Powell et al. Nature Communications


Transcriptomic and proteomic retinal pigment epithelial signatures of age-related macular degeneration

Currently, there are no treatments for geographic atrophy, an advanced form of age-related macular degeneration. Therefore, innovative research is needed to model this condition and prevent or delay its development.

Induced pluripotent stem cells from patients with geographic atrophy and healthy individuals differentiated into retinal pigment epithelium. By integrating transcriptional profiles of 127,659 retinal pigment epithelial cells from 43 individuals with geographic atrophy and 36 controls with genotype data, we identify 445 expression quantitative marker loci in cis that are associated with disease states and specific to retinal pigment epithelial subpopulations.

Transcriptomics and proteomics approaches identify molecular pathways significantly upregulated in geographic atrophy, including mitochondrial functions, metabolic pathways, and extracellular matrix reorganization.

Five important protein-encoded marker loci have been identified that regulate protein expression in the retinal pigment epithelium and geographic atrophy—two of which share variants with cis-expression marker loci, including proteins in mitochondrial biology and neurodegeneration. Mitochondrial metabolism studies confirm mitochondrial dysfunction as a major constitutive difference in retinal pigment epithelium from patients with geographic atrophy.

This study reveals important differences in retinal pigment epithelium homeostasis associated with geographic atrophy.

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