Hydrogen Sulfide and β-Synuclein Are Involved and Interlinked in the Aging Glaucomatous Retina

Abstract

Purpose. Glaucoma, one of the leading causes of irreversible blindness worldwide, is a group of disorders characterized by progressive retinal ganglion cell (RGC) loss. Synucleins, a family of small proteins, have been of interest in studies of neurodegeneration and CNS. However, their roles and functions in glaucoma are still not completely understood and remain to be explored. Our previous studies showed that α-synuclein and H2S play a pivotal role in glaucoma. This study aims to (1) elucidate the potential roles and functions of synucleins in glaucoma throughout aging, (2) investigate the interaction between the synucleins and H2S, and better understand the mechanism of H2S in neuroprotection. Methods. The chronic IOP elevation model was carried out in 12 animals at different ages (3 months and 14 months), and RGCs were quantified by Brn3a staining. Mass spectrometric-assisted proteomics analysis was employed to measure synuclein levels and H2S producing proteins in retina. Secondly, the acute IOP elevation model was carried out in 12 juvenile animals, with or without intravitreal injection of GYY4137 (a H2S donor). RGCs were quantified along with the abundancy of synucleins. Results. RGCs and β-synuclein (SNCB) are significantly changed in old animals. Under chronic IOP elevation, there is a significant RGC loss in old animals, whereas no significant change in young animals; SNCB is significantly downregulated and 3MST is significantly upregulated in young animals due to IOP, while no significant changes in old ones are notable. Under acute IOP elevation (approx. 55 mmHg), a significant RGC loss is observed; exogenous H2S significantly reduced RGC loss and downregulated SNCB levels. Conclusion. The present study indicates a strong link between ageing and SNCB regulation. In young animals SNCB is downregulated going along with less RGC loss. Furthermore, increasing endogenous H2S is effective to downregulate SNCB and is neuroprotective against acute IOP elevation.

Alpha and Beta Synucleins: From Pathophysiology to Clinical Application as Biomarkers

“…68,69 β-Synuclein and γ-synuclein are expressed in retinal neurons and have been associated with glaucoma-related neurodegeneration. 70,71 To date, no convincing hypothesis has been proposed for the roles of β-synuclein in neurons, but it may act as a general synaptic chaperone. 72 In adrenal chromaffin cells, it regulates vesicle dynamics and secretory rate with mechanisms similar to those occurring in neurons.…”

Hydrogen Sulfide Protects Retinal Pigment Epithelial Cells from Oxidative Stress-Induced Apoptosis and Affects Autophagy

“…H 2 S has been reported to have diverse physiologic functions, such as vasodilatation, lowering blood pressure, anti-inflammation, anti-cancer, and reducing oxidative stress [ 11 , 13 ]. Moreover, H 2 S is produced in retinal tissue and attenuates high glucose-induced human retinal pigment epithelial cell inflammation by inhibiting ROS formation [ 12 ], but some studies also illustrate H 2 S-caused retinopathy [ 14 , 15 ].…”

Proteomics Reveals the Potential Protective Mechanism of Hydrogen Sulfide on Retinal Ganglion Cells in an Ischemia/Reperfusion Injury Animal Model

“…Furthermore, we demonstrated that administration of GYY4137, a slow-release H 2 S donor, significantly improved RGC survival under different glaucomatous injuries in vitro and in vivo [ 21 ]. The neuroprotective effect of H 2 S in the retina was partly attributed to its capability of vasorelaxation, anti-oxidative stress, neuroendocrine regulation and inflammation suppression [ 25 ] but the underlying mechanism and the specific protein interaction networks and the mechanisms involved in protective properties of H 2 S remain to be elucidated. Building on previous results, we employed a mass spectrometry-based proteomics approach to analyze the retinal proteome, and bio-informatics to algorithmically generate protein connections, which allowed us to identify the most plausible signaling pathway alterations related to H 2 S’s neuroprotective properties against ischemia-reperfusion injury in present study.…”