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Abstract #127589 Published in IGR 25-3
A role of pigment epithelium-derived factor in zinc-mediated mechanism of neurodegeneration in glaucoma
Chistyakov DV; Belousov AS; Shevelyova MP; Iomdina EN; Baksheeva VE; Shebardina NG; Moysenovich AM; Bulgakov TK; Petrov SY; Petrov SY; Petrov SY; Petrov SY; Shishkin ML; Tulush SS; Tiulina VV; Pogodina EI; Gancharova OS; Filippova OM; Baldin AV; Goriainov SV; Nikolskaya AI; Zalevsky AO; Deviatkin AA; Vologzhannikova AA; Gorokhovets NV; Litus EA; Komarov SV; Devred F; Sergeeva MG; Mishin AV; Bukhdruker SS; Wu L; Araujo EA; Zamyatnin AA; Senin II; Zinchenko DV; Tsvetkov PO; Borshchevskiy VI; Permyakov SE; Zernii EYCommunications biology 2025; 8: 965
Glaucoma is a neurodegenerative condition involving optic nerve damage and retinal ganglion cells death. Animal studies suggested that the pathway linking these events can be mediated by mobile zinc secreted into the intraretinal space and exerting cytotoxic effects. Whether this mechanism is relevant for human glaucoma and what are the targets of extracellular zinc is unknown. We report that increased zinc content in the aqueous humor and retina is indeed a characteristic of glaucomatous neuropathy, and excess extracellular zinc may be recognized by the key retinal neurotrophic factor PEDF. Biophysical and X-ray crystallographic studies show that PEDF coordinates zinc ions in five types of intermolecular high-affinity sites, leading to a decrease in negative surface charge and reversible oligomerization of the protein, thereby masking the target recognition sites responsible for its neurotrophic and antiangiogenic activities and collagen binding. Notably, PEDF secretion is enhanced in both glaucoma and retinal cell models in response to zinc stress; however, zinc binding negatively affects axogenic, differentiative and prosurvival functions of PEDF by suppressing its ability to activate receptor PEDF-R/PNPLA2. We suggest that glaucomatous neurodegeneration is associated with direct inhibition of PEDF signaling by extracellular zinc, making their complex a promising target for neuroprotective therapy.
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