A recent mouse study from the National Eye Institute suggests that the depletion of the protein pigment epithelium-derived factor (PEDF), which safeguards retinal support cells, may be the cause of age-related alterations in the retina (NEI).
The light-sensitive tissue called the retina is located in the back of the eye, and age-related retinal illnesses such age-related macular degeneration (AMD) can cause blindness.
This brand-new discovery may result in treatments for AMD and other ageing retinal disorders. International Journal of Molecular Sciences published the study. The National Institutes of Health includes NEI.
“People have called PEDF the ‘youth’ protein because it is abundant in young retinas, but it declines during aging,” said Patricia Becerra, Ph.D., chief of NEI’s Section of Protein Structure and Function and senior author of the study. “This study showed for the first time that just removing PEDF leads to a host of gene changes that mimic aging in the retina.”
The retina is made up of layers of cells that work in concert to recognise and interpret light signals, which the brain uses to produce vision. The retina’s light-sensing photoreceptors are located above a layer of support cells called the retinal pigment epithelium (RPE).
When photoreceptors perceive light, the RPE nourishes them and recycles “outer segments,” which are used up and lost from the tips of photoreceptor cells. Photoreceptor cells lose their capacity to generate new segments if the RPE is unable to deliver recycled parts of worn-out outer segment tips back to them, and they eventually lose their capacity to detect light. Additionally, photoreceptors die if they are not fed nutrients by the RPE.
Senescence (ageing) or RPE cell death in the retina causes visual loss in persons with AMD or certain types of retinal dystrophies.
According to earlier research from Becerra’s lab and others, PEDF shields retinal cells against harm and aberrant blood vessel formation in the retina. The PEDF protein is produced and secreted by RPE cells. After then, the protein interacts to the PEDF-R receptor, which is also produced by RPE cells. When PEDF binds to PEDF-R, PEDF-R is stimulated to degrade lipid molecules, important building blocks of cell membranes that surround photoreceptor outer segments and other cellular compartments.
A crucial step in the recycling of outer segments is this breakdown stage. It was also unclear if the decline in PEDF levels in the retina during ageing actually caused or was merely correlated with changes in the retina that are associated with ageing.
Becerra and associates used a mouse strain lacking the PEDF gene to investigate the function of PEDF in the retina (Serpin1). The RPE cell nuclei were found to be bigger when the researchers looked at the cellular structure of the mouse model’s retina. This discovery may be related to alterations in the way the cells’ DNA is organised.
Additionally, four genes linked to ageing and cellular senescence had been activated in the RPE cells, and the PEDF receptor was drastically below normal levels. Finally, the RPE layer of the retina had accumulated unprocessed lipids and other photoreceptor outer segment constituents. The aged retina has similar abnormalities in RPE metabolism and alterations in gene expression.
“One of the most striking things was this reduction in the PEDF receptor on the surface of the RPE cells in the mouse lacking the PEDF protein,” said the study’s lead author, Ivan Rebustini, Ph.D., a staff scientist in Becerra’s lab. “It seems there’s some sort of feedback-loop involving PEDF that maintains the levels of PEDF-R and lipid metabolism in the RPE.”
These new findings imply that PEDF is playing a protective role that aids the retina in withstanding damage and aging-related wear and tear, even if the retinas of these PEDF-negative mice first appear normal.
“We always wondered if loss of PEDF was driven by aging, or was driving aging,” said Becerra. “This study, especially with the clear link to altered lipid metabolism and gene expression, indicates the loss of PEDF is a driver of aging-related changes in the retina.”