In a rare eye disease, the retina degenerates because light-receiving cells fail to regenerate, research led by a student at Case Western Reserve University School of Medicine shows.
The researchers include Dr. Samuel G. Jacobson's group at the University of Pennsylvania and Dr. Andreas Engel's group at University of Basel, Switzerland. They found that when the natural renewal process fails, metabolites are locked in, build up and turn toxic, killing cells over time in Enhanced S-Cone Syndrome.
A description of their work is online and will be published in print in the Journal of the Federation of American Societies for Experimental Biology today.
The discovery provides a target to treat and prevent blindness caused by the disease, also known as Goldmann-Favre Syndrome, which is found in about one in 1 million people.
But, more importantly the researchers say, the findings and the scientists' use of two technologies to uncover the mechanisms leading to sight loss may help gain understanding of a broad array of retinal degenerative diseases, including macular degeneration, affecting millions worldwide.
"Although rare, Enhanced S-Cone Syndrome helps us understand critical visual processing errors that arise in disease," said Debarshi Mustafi, who is earning his medical degree and PhD in pharmacology at Case Western Reserve. He is lead author of the study. "Knowing that photoreceptor cells affect their own renewal will surely have an impact on other, more common, forms of retinal degeneration."
Enhanced S-Cone Syndrome is a condition in which the eye no longer has an orderly balance of cells called rods and cones, which enable us to see lights of different wavelengths, that is, different colors. Instead, cones that receive short wavelength light dominate and are clumped throughout the retina.
Those with the disease become night blind and progressively develop blind spots and lose sight as they age, until reaching blindness.
Genes connected to the disease have been known for some time. To find the molecular mechanism that causes sight loss, the researchers examined mouse models of the disease and 9 patients with the syndrome.
Optical imaging of the patients over a decade revealed an abnormal interface between the cones and the adjacent layer of tissue, called the retinal pigment epithelium.
Using gene-sequencing techniques on the mouse models, the team found expression of 30 genes involved in sight differed in healthy mice versus the disease models. Three of the genes were engaged in renewal of photoreceptors, a process called phagocytosis.
The researchers used a scanning electron microscope to produce images down to 100 nanometers, or the size of the largest holes in a surgical mask.
They found no phagosomes, essentially compartments made in cone cell membranes in which specialized cells called phagocytes of the retinal pigment epithelium eat cone material. In a healthy retina, phagosomes are present; phagocytes eat about 10 percent of the cone per day, continually renewing the cone.
The images instead showed bulbous cones in which metabolites that would normally be consumed remain, causing the swelling and turning toxic, the researchers said.
Analysis of cell cultures confirmed aberrations in the cones themselves were the cause of the problem, not the adjacent pigment layer as was previously thought.
"What we learn from this inherited human disease, and its mouse model, will be helpful to understand the aging process of the retina, like that seen in age-related macular degeneration," said Krzysztof Palczweski, John H. Hord Professor and chair of the Department of Pharmacology at CWRU School of Medicine. Palzcweski is Mustafi's advisor and senior author of the paper. "It is very likely that the phagocytotic process described in Debarshi's paper is a dysfunction as we age."
Mustafi said the methods that led to the discovery - combining gene sequencing and imaging - may have a wider impact. "It is a new way to study any disease."