Bunkers that save sight? Researchers take a close look
Support cells in the retina do their best to sequester damaged proteins
away from cells responsible for vision, preserving sight as long as possible


Date:
March 8, 2022
Source:
University of Connecticut
Summary:
Chronically stressing the retina can weaken it and damage our
ability to see. But retinal cells have a remarkable ability to wall
off damage, a team of neuroscientists reports. The walling-off or
'bunkering' of the damage may be key to preserving our eyesight.



FULL STORY ========================================================================== Chronically stressing the retina can weaken it and damage our ability
to see.

But retinal cells have a remarkable ability to wall off damage, a team
of neuroscientists led by UConn Health reports in the 1 March issue
of PNAS. The walling-off or "bunkering" of the damage may be key to
preserving our eyesight.


==========================================================================
The retina is a delicate tissue in the back of the eye that detects
light and transmits images to the brain. Muller glia are very long cells
that span the thickness of the retina and provide mechanical strength, supporting the neurons and light receptors that detect light, shape
and color.

Muller glia are also involved in protein changes related to retinal
injury, being the first cells to respond. UConn School of Medicine neuroscientist Royce Mohan and colleagues have discovered that the
endfeet, a specialized zone in Muller cells, is where proteins become
modified when the retina is under stress. These endfeet are at the
opposite end of the retina, quite a distance from light receptors. The researchers propose in the paper that this segregation of the endfeet
and light receptors may permit light detection to continue even as the
retina responds to stress.

The modification of proteins Mohan's lab has been studying is called citrullination. In citrullination, the amino acid arginine is changed
into citrulline. Because in early stages of stress or disease, the citrullinated proteins stay sequestered in the Muller cells' endfeet,
Mohan calls this area the citrullination bunker. But if this bunker is chronically engaged, then the overabundance of citrullinated proteins
reach other parts of the retina. Muller cells in human age-related
macular degeneration (AMD) and mouse models of retinal degeneration
reveal citrullinated proteins extending out of the endfeet and spreading throughout the cells.

Citrullination may have many effects on Muller glial cells which are
only just being understood. For example, arginine is positively charged,
while citrulline is not. The loss of the positive charges is permanent,
and may irreversibly change the flexibility or other mechanical properties
of the Muller glial cells. This may cause the Muller cells to become
incapable of adapting to fluid build-up when the retina swells up under
stress. Alternatively, it's possible the citrullinated proteins could
appear foreign to the body and draw the attention of the immune system, potentially beginning autoimmune disease.

Turning off citrullination in the end feet bunker could delay or avoid
these problems and preserve eyesight for longer.

This team has also identified that the endfeet citrullination process
is controlled by an enzyme known as peptidyl arginine deiminase-4
(PAD4). Small molecule inhibitors of PAD4 have been developed for
other types of citrullination-dependent diseases, such as rheumatoid
arthritis. Mohan believes that such therapeutic agents could be applied
to reduce citrullination at early stages of AMD and spare the retina of undesired responses to this protein modification.


========================================================================== Story Source: Materials provided by University_of_Connecticut. Original
written by Kim Krieger. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Sarah I. Palko, Nicholas J. Saba, Elias Mullane, Benjamin
D. Nicholas,
Yosuke Nagasaka, Jayakrishna Ambati, Bradley D. Gelfand, Akihito
Ishigami, Paola Bargagna-Mohan, Royce Mohan. Compartmentalized
citrullination in Muller glial endfeet during retinal degeneration.

Proceedings of the National Academy of Sciences, 2022; 119 (9)
DOI: 10.1073/pnas.2121875119 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/03/220307162016.htm

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