A role of pigment epithelium-derived factor in zinc-mediated mechanism of neurodegeneration in glaucoma

Chistyakov, D.V.; Belousov, A.S.; Shevelyova, M.P.; Iomdina, E.N.; Baksheeva, V.E.; Shebardina, N.G.; Moysenovich, A.M.; Bulgakov, T.K.; Petrov, S.Y.; Shishkin, M.L.; Tulush, S.S.; Tiulina, V.V.; Pogodina, E.I.; Gancharova, O.S.; Filippova, O.M.; Baldin, A.V.; Goriainov, S.V.; Nikolskaya, A.I.; Zalevsky, A.O.; Deviatkin, A.A.; Vologzhannikova, A.A.; Gorokhovets, N.V.; Litus, E.A.; Komarov, S.V.; Devred, F.; Sergeeva, M.G.; Mishin, A.V.; Bukhdruker, S.S.; Wu, L.; Araujo, E.A.; Zamyatnin Jr, A.A.; Senin, I.I.; Zinchenko, D.V.; Tsvetkov, P.O.; Borshchevskiy, V.I.; Permyakov, S.E.; Zernii, E.Y.

Авторы: Chistyakov Dmitry V., Belousov Anatolii S., Shevelyova Marina P., Iomdina Elena N., Baksheeva Viktoriia E., Shebardina Natalia G., Moysenovich Anastasia M., Bulgakov Timofey K., Petrov Sergey Yu, Shishkin Mikhail L., Tulush Sanchay S., Tiulina Veronika V., Pogodina Ekaterina I., Gancharova Olga S., Filippova Olga M., Baldin Alexey V., Goriainov Sergey V., Nikolskaya Arina I., Zalevsky Arthur O., Deviatkin Andrei A., Vologzhannikova Alisa A., Gorokhovets Neonila V., Litus Ekaterina A., Komarov Sergey V., Devred François, Sergeeva Marina G., Mishin Alexey V., Bukhdruker Sergey S., Wu Lijie, Araujo Evandro A., Zamyatnin Jr Andrey A., Senin Ivan I., Zinchenko Dmitry V., Tsvetkov Philipp O., Borshchevskiy Valentin I., Permyakov Sergei E., Zernii Evgeni Yu
Журнал: Communications Biology
Том: 8
Год издания: 2025
Издательство: Springer Nature
Местоположение издательства: Switzerland
Номер статьи: 965
DOI: 10.1038/s42003-025-08370-8
Аннотация: 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.
Добавил в систему: Булгаков Тимофей Кириллович

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