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.
Highlights
Glaucoma, one of the leading causes of irreversible blindness worldwide [1], is a group of disorders characterized by progressive retinal ganglion cell (RGC) loss and axon atrophy, which leads to gradually visual field loss [2]
No noticeable difference in intraocular pressure (IOP) was observed between age groups. e untreated contralateral eyes remained unaffected in terms of IOP changes [52] (∗∗∗p < 0.001, n 12, mean ± SD)
As predominantly elder people are affected in glaucoma, older animals showed a higher susceptibility to IOP elevation resulting in significant loss of RGCs and retinal nerve fiber layer (RNFL) thickness, while younger animals seemed to show resistance against mildly elevated IOP
Summary
One of the leading causes of irreversible blindness worldwide [1], is a group of disorders characterized by progressive retinal ganglion cell (RGC) loss and axon atrophy, which leads to gradually visual field loss [2]. By far the only known modifiable risk factor of glaucoma is intraocular pressure (IOP); lowering IOP is not able to halt the deterioration of glaucoma in most patients in clinic practice, indicating again the multifactorial pathogenesis and the complexity of glaucoma [3]. Alternative approaches independent of IOP and probably combating aging as well as focusing on the pathophysiological processes are in demand to ameliorate glaucoma neuropathy. Other pathophysiological processes including oxidative stress, inflammatory reaction, glial activation, vascular dysfunctions, and abnormal protein accumulation are proven to be closely involved [4,5,6,7]. H2S plays critical roles in multiple physiological and pathological processes, it works to alleviate inflammatory responses and oxidative stress and restores energy
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