Citrullination Bunker in Müller Glia Endfeet Preserves Sight in Early Stages of Retinal Stress

Article: Bunkers That Save Sight? Researchers Take a Close Look
Source: University of Connecticut
Published: March 8, 2022

Wet-AMD human retina (bottom) showing citrullination localized 
at Müller cell endfeet (M and N stained for a citrullination targeting
protein and its citrullinated form in green and red, respectively)
compared to control human retina (top)

Müller glia are support cells that axially span the retina from its inner surface (the inner limiting membrane) to the base of the photoreceptors. These support cells have properties that aid in mechanical strength and response to cellular stress (reactive gliosis) as well as channeling incoming light to the photoreceptors, where light is transduced to electrical signals to be sent to the brain. Scientists studying Müller glia in retinal laser injury, a genetically modified mouse model, and in human wet-AMD tissues recently discovered that the endfeet of these cells, specifically at the end opposite to the photoreceptors, also possess the ability to sequester cellular stress in the early stages of retinal degeneration before it affects the photoreceptors. At the endfeet of Müller cells, proteins become modified in a process called citrullination, in which the amino acid arginine is changed into citrulline, when the retina is under stress. The researchers hypothesize that this process is due in part to the difference in charge between arginine, which is positively charged, and citrulline, which is not, and that the loss of positive charge changes the mechanical properties of the cell such that it is less able to adapt to fluid build-up when the retina is under stress. Alternatively, it's possible that citrulline is seen as foreign to the body and triggers an autoimmune response. Citrullination can spread to affect the rest of the cell and neighboring cells, such as in later stages of disease, e.g., in age-related macular degeneration (AMD). However, this study emphasizes that the "bunkering" of citrullination in the Müller cells' endfeet, far from the photoreceptors, permits light detection to continue even as the retina responds to early stress. The team identified that the citrullination is controlled by the enzyme peptidyl arginine deiminase-4 (PAD4), and development of inhibitors of PAD4 could delay or prevent disease progression at early stages to preserve eyesight for longer.

My rating of this study: ⭐⭐⭐

Palko SI, Saba NJ, Mullane E, et al. "Compartmentalized citrullination in Muller glial endfeet during retinal degeneration." PNAS.  119(9):e2121875119. 23 February 2022. https://doi.org/10.1073/pnas.2121875119