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

Introduction

Zinc is a key micronutrient that is essential for many aspects of neuronal function, such as direct mediation of neurotransmission^1,2. Although the total concentration of zinc in the nervous system is remarkably high, healthy neurons contain only trace amounts of free Zn²⁺ since its excess is excreted from the cytoplasm by specific Zn²⁺-transporting proteins (ZnTs) into mitochondria, lysosomes or specific vesicles (zincosomes), and/or coordinated by Zn²⁺-buffering proteins (e.g., metallothioneins)². The remaining zinc is incorporated into complexes with numerous Zn²⁺-binding proteins and, depending on binding affinity, can play a structural and functional role or exhibit signaling activity by being redistributed among signal transduction proteins (so-called “mobile” or “loosely bound” zinc)^{3, 4–5}. When zinc homeostasis is disturbed, it becomes a pathological factor causing irreversible neurodegenerative changes in the central nervous system and retina^4,6. In particular, the pronounced aberrant activity of excess zinc may be realized in the interneuron space. Even under normal conditions, zinc concentration in the synaptic cleft can transiently increase from 15–20 nM to 10–300 μM and disruption of its reuptake can significantly affect cell viability^2,5,7.

Glaucoma is a neurodegenerative disease, one of the leading causes of irreversible blindness. It has a complex pathogenesis, which is always characterized by damage to the optic nerve with subsequent death of retinal ganglion cells (RGCs), the projection neurons of the eye. The most common form of the disease is primary open-angle glaucoma (POAG), the main risk factor for which is a transient or persistent increase in intraocular pressure (IOP) caused by obstruction of aqueous humor (AH) outflow through the trabecular meshwork and Schlemm’s canal in the anterior chamber angle and/or through the uveoscleral pathway. Chronic ocular hypertension leads to cupping of the optic nerve head into the lamina cribrosa and subsequent death of RGCs due to the inability to regenerate their axons constituting the optic nerve⁸. Early stages of POAG are asymptomatic and the emerging disease can be recognized only using sophisticated biomarker-based approaches^9,10. Meanwhile, manifestation of the symptoms, such as narrowing of the visual fields, indicates an irreversible neurodegenerative process, which is poorly treated. It is noteworthy that the multifactorial nature of POAG hinders the development of...