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Uncovering genetic clues to age-related macular degeneration – Neuroscience News

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

source: Garvan Institute

Better diagnosis and treatment of age-related intractable eye disease is a step closer, thanks to the discovery of new genetic hallmarks of the disease.

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

We tested the way differences in people’s genes affect cells involved in age-related macular degeneration. On a smaller scale, we have narrowed down specific cell types to identify genetic markers for this disease, says co-lead author Professor Joseph Powell, director of Garvan’s Cell Science Column.

“This is the basis of precision medicine, where we can then look at the treatments that may be most effective for the genetic profile of the disease.”

Age-related macular degeneration, or AMD, is the gradual deterioration of the macular — an area in the center of the retina toward the back of the eye — resulting in impairment or possible loss of central vision. About one in seven Australians over the age of 50 are affected, and about 15 percent of those over 80 have vision loss or blindness.

The reasons behind the decline remain elusive, but genetic and environmental factors contribute to it. Risk factors include age, family history, and smoking.

The research was published today in the journal Nature Connections.

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

Retinal pigment epithelial cells line the back of the retina and are essential for the health and functioning of the retina. Its degeneration is associated with the death of photoreceptors, which are light-sensitive neurons in the retina that transmit visual signals to the brain and are responsible for the vision loss in AMD.

Analysis of 127,600 cells revealed 439 molecular signatures associated with AMD, 43 of which are potential novel genetic variants. The major intracellular pathways identified were subsequently tested and revealed differences in energy-producing mitochondria between healthy and AMD cells, making mitochondrial proteins potential targets for preventing or altering the AMD pathway.

Black and white electron microscopy of retinal pigment epithelium cells. Credit: Dr. Grace Ledgerwood

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

Ultimately, we are interested in matching a patient’s genetic profile to the best drug for that patient. We need to test how it works in cells relevant to the disease,” says study co-leader Professor Alice Paybay, from the University of Melbourne.

Professor Powell and co-lead authors Professor Pébay and Professor Alex Hewitt from the Menzies Institute for Medical Research in Tasmania and the Eye Research Center in Australia have a long-standing collaboration to investigate the genetic causes underlying complex human diseases.

“We have built a research program where we are interested in stem cell studies for disease modeling at a very large scale to screen for future clinical trials,” says Professor Hewitt.

In another recent study, researchers unveiled the genetic markers for glaucoma – a degenerative eye disease that causes blindness – using stem cell models of the retina and optic nerve.

Researchers are also turning their attention to the genetic causes of Parkinson’s disease and cardiovascular disease.

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About this genetics and vision research news

author: press office
source: Garvan Institute
Contact: Press Office – Garvan Institute
picture: Photo credited to Grace Ledgerwood

original search: open access.
Transcriptional and proteomic retinal epithelium signatures of age-related macular degenerationWritten by Joseph Powell et al. Nature Connections


Transcriptional and proteomic retinal epithelium signatures of age-related macular degeneration

There are currently no treatments for geographic atrophy, the advanced form of age-related macular degeneration. Thus, innovative studies are needed to model this condition and prevent or delay its progression.

The induced pluripotent stem cells generated from patients with geographic atrophy and healthy individuals have been differentiated into the retinal pigment epithelium. By integrating transcriptome profiles of 127,659 retinal pigment epithelial cells generated from 43 individuals with geographic atrophy and 36 controls with genotype data, we identify 445 loci for quantitative trait expression in disease-status-associated cis-specific subpopulations of retinal epithelium. .

Transcriptional and proteomic approaches identify molecular pathways that are significantly upregulated in geographic atrophy, including mitochondrial functions, metabolic pathways, and reorganization of the cellular extracellular matrix.

Five important quantitative protein loci that regulate protein expression in the retinal pigment epithelium and in geographic atrophy have been identified—two of which share variants with quantitative trait loci, including proteins involved in mitochondrial biology and neurodegeneration. Investigation of mitochondrial metabolism confirms that mitochondrial dysfunction is the primary constitutive variation of the 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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