Аннотация:Retinal degenerative disorders represent an urgent problem of modern ophthalmology, as damage to retinal neurons leads to irreversible and currently incurable loss of vision. The central place among such disorders is held by glaucoma, an optical neuropathy characterized by multifactorial pathogenesis and lack of specific therapy. A breakthrough in understanding glaucoma pathogenesis was the recognition of mobile zinc as a potential mediator of retinal and optic nerve degeneration. This discovery is particularly important in light of the recent identification of the signaling function of zinc in the cytoplasm and extracellular space and the interconnection of zinc-dependent pathways with calcium signaling. In the present work, we addressed glaucoma mechanisms using animal model of the disease, cellular and biochemical studies, and structural approaches based on machine learning and X-ray crystallographic analysis, identifying novel zinc-dependent extracellular targets in this disease. It was shown for the first time that secreted zinc suppresses neurotropic activity in the retina by affecting the processing of the signaling factors involved and their interaction with cell surface receptors. The discovered mechanism may be common to a wide range of neurodegenerative diseases and become a target for various treatment options, including gene therapy. This work was supported by the Russian Science Foundation Grant No. 24-15-00171.
