The retina, the inner lining of the eye, is particularly vulnerable to genetic and environmental changes that cause oxidative stress and damage photoreceptor cells and retinal neurons, ultimately leading to their death. Scientists know about 90 genes associated with retinitis pigmentosa, one of which is CERKL (CERamide Kinase-Like). Mutations in this gene cause retinitis pigmentosa and rod-cone dystrophy. Both diseases are characterized by photoreceptor degeneration and progressive vision loss. The CERKL gene is responsible for resistance to oxidative stress. Its overexpression protects cells from death due to oxidative stress. CERKL also participates in the formation stress granules and regulates mitochondrial dynamics in the retina.
The retina is constantly exposed to light, and therefore oxidative stress. To cope with it, its cells must activate antioxidant mechanisms. A group of scientists led by Professor Gemma Marfani (Gemma Marfany) from the Institute of Biomedicine of the University of Barcelona. Their work published magazine Redox Biology.
For the study, the scientists used adult transgenic albino mice in which the CERKL gene was removed using the CRISPR-Cas9 genetic engineering method. Experiments on them using electrophysiological methods showed for the first time that in the absence of the CERKL gene, retinal cells continuously experience stress and progressively degenerate, as happens in people with retinitis pigmentosa.
In the absence of the CERKL gene, the retinal cells of transgenic mice continuously experienced stress and degenerated / © Gemma Marfany et al.
During the experiments, mice were anesthetized with a mixture of ketamine and xylazine, and then one eye, previously instilled with cyclopentolate to dilate the pupil, was exposed to white light at 3000 lux for an hour. The second eye was closed at the same time to be used as a control point. At the end of the procedure, the mice were immediately sacrificed, and the scientists examined the early response to light stress in the resulting retina. In another series of experiments, which studied the late response to stress, both eyes were exposed to light at once, and the rodents were sacrificed to obtain retinal tissue two weeks later.
“With additional oxidative damage—as is the case with prolonged light stimulation—the cells are no longer able to respond because they cannot activate the antioxidant response mechanisms. For this reason, the retina is constantly inflamed. As a result, the mechanisms of cell death – necroptosis and ferroptosis – are activated in retinal cells,” told Gemma Marfani.
She added that although the experiments were carried out on mice, the changes identified in the retina help explain how and why photoreceptor cells die in patients with retinitis pigmentosa, causing blindness.
The scientists called their results important because they complement existing genetic research and open the way to the development of new approaches to the treatment of hereditary eye diseases. Retinitis pigmentosa is the most common form of hereditary retinal dystrophy. In general, diseases of this group occur in one person out of three thousand in the world.
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