Glaucoma is a chronic blinding eye disease caused by the progressive loss of retinal ganglion cells (RGCs). Currently, no clinically approved treatment can directly improve the survival rate of RGCs. The Apolipoprotein E (APOE) gene is closely related to the genetic risk of numerous neurodegenerative diseases and has become a hot topic in the field of neurodegenerative disease research in recent years. The optic nerve and retina are extensions of the brain\'s nervous system. The pathogenesis of retinal degenerative diseases is closely related to the degenerative diseases of the nerves in the brain. APOE consists of three alleles, ε4, ε3, and ε2, in a single locus. They have varying degrees of risk for glaucoma. APOE4 and the APOE gene deletion (APOE-/-) can reduce RGC loss. By contrast, APOE3 and the overall presence of APOE genes (APOE+/+) result in significant loss of RGC bodies and axons, increasing the risk of glaucoma RGCs death. Currently, there is no clear literature indicating that APOE2 is beneficial or harmful to glaucoma. This study summarises the mechanism of different APOE genes in glaucoma and speculates that APOE targeted intervention may be a promising method for protecting against RGCs loss in glaucoma.

Retinal ischemia, after cerebral ischemia, is an easily overlooked pathophysiological problem in which inflammation is considered to play an important role. Pyroptosis is a kind of cell death pattern accompanied by inflammation. Homer scaffold protein 1 (Homer1) has anti-inflammation properties and protects against ischemic injury. However, little is known about pyroptosis following middle cerebral artery occlusion (MCAO)-induced retinal ischemia and the regulatory mechanisms involved by Homer1 for the development of pyroptosis. In the present study, retinal ischemic injury was induced in mice by permanent MCAO in vivo, and retinal ganglion cells (RGCs) were subjected to Oxygen and Glucose Deprivation (OGD) to establish an in vitro model. It was shown that TXNIP/NLRP3-mediated pyroptosis was located predominantly in RGCs, which gradually increased after retinal ischemia and peaked at 24 h after retinal ischemia. Interestingly, the RGCs pyroptosis occurred not only in the cell body but also in the axon. Notably, the occurrence of pyroptosis coincided with the change of Homer1 expression in the retina after retinal ischemia and Homer1 also co-localized with RGCs. It was demonstrated that overexpression of Homer1 not only alleviated RGCs pyroptosis and inhibited the release of pro-inflammatory factors but also led to the increase in phosphorylation of AMPK, inhibition of ER stress, and preservation of visual function after retinal ischemia. In conclusion, it was suggested that Homer1 may protect against MCAO-induced retinal ischemia and RGCs pyroptosis by inhibiting endoplasmic reticulum stress-associated TXNIP/NLRP3 inflammasome activation after MCAO-induced retinal ischemia.

Glaucoma is an eye disease with a high rate of blindness and a complex pathogenesis. Ocular hypertension (OHT) is a critical risk factor, and retinal ischemia/reperfusion (I/R) is an important pathophysiological basis. This study was designed to investigate the retinal neuroprotective effect of oral naringenin in an acute retinal I/R model and a chronic OHT model and the possible mechanism involved. After the I/R and OHT models were established, mice were given vehicle or naringenin (100 mg/kg or 300 mg/kg). Hematoxylin-eosin (HE) staining and immunostaining of RBPMS and glial fibrillary acidic protein (GFAP) were used to evaluate retinal injury. GFAP, CD38, Sirtuin1 (SIRT1), and NOD-like receptor protein 3 (NLRP3) expression levels were measured by Western blotting. In the OHT model, intraocular pressure (IOP) was dynamically maintained at approximately 20-25 mmHg after injury. The retinal structure was damaged, and retinal ganglion cells (RGCs) were lost in both models. Naringenin ameliorated the abovementioned indications but also demonstrated that high concentrations of naringenin significantly inhibited retinal astrocyte activation and inhibited damage-induced increases in the expression of GFAP, NLRP3, and CD38 proteins, while SIRT1 protein expression was upregulated. This study showed for the first time that naringenin can reduce microbead-induced IOP elevation in the OHT model, providing new evidence for the application of naringenin in glaucoma. Naringenin may mediate the CD38/SIRT1 signaling pathway, inhibit astrocyte activation, and ultimately exert an anti-inflammatory effect to achieve retinal neuroprotection.

To analyze the functional and structural changes in retinal ganglion cells (RGCs) and their axons that occur during Leber\'s hereditary optic neuropathy (LHON) using photopic negative response (PhNR) and spectral domain optical coherence tomography (SD-OCT).
Individuals diagnosed with LHON and their family members were invited to participate in this cross-sectional study. PhNR and OCT were used. The PhNR amplitude and peripapillary retinal nerve fiber layer (pRNFL) thicknesses were compared among the three groups. In addition, affected individuals were divided into subacute, dynamic and chronic phases based on disease duration in order to evaluate the decay in RGCs function and structure.
73 affected and 30 carriers with a m.11778G > A mutation were included. PhNR amplitude and the thickness of pRNFL significantly decreased in affected individuals and carriers compared to that of the controls (P＜0.001). However, there was no difference between the carriers and the controls (P＞0.05). There was no difference in the PhNR amplitude of different phases (P = 0.464). In the subacute phase, only temporal pRNFL thickness decreased significantly (P＜0.001). PRNFL thickness decreased significantly in dynamic phase (P＜0.001). Temporal pRNFL thickness continued to decrease in the chronic phase (P = 0.042).
In the subacute phase, the function of RGCs was severely impaired. Thickness of pRNFL decreased significantly in four quadrants during disease progression. In the chronic phase, pRNFL thickness decreased slightly. Carriers have shown RGCs dysfunction before pathological changes occur, suggesting subclinical abnormalities.

Retinal ganglion cells (RGCs) apoptosis is a vital manifestation of retinal ischemia/reperfusion (I/R) injury, yet the underlying mechanisms are not well understood. The contribution of long noncoding RNAs (lncRNAs) to this cellular process is currently being explored. Based on a lncRNA chip assay, we aimed to investigate the role of lncRNA uc007nnj.1 in the pathological process of ischemia-induced RGCs apoptosis.
Hank\'s balanced salt solution containing 10 µM antimycin A and 2 µM calcium ionophore for 2 h to construct an ischemic model in RGCs, and elevation of intraocular pressure to 120 mm Hg for 1 h was used to construct a mouse model of retinal I/R injury.
In this study, lncRNA uc007nnj.1 was highly upregulated in response to I/R injury in RGCs and mouse retinas. In addition, lncRNA uc007nnj.1 knockdown reduced retinal neuronal cell apoptosis in vitro and in vivo and significantly improved retinal function.
Mechanistically, the results demonstrated that lncRNA uc007nnj.1 acts as ceRNA competitively binding miR-155-5p, thereby enhancing the expression levels of Tle4, thus aggravating ischemia-related apoptosis in RGCs.
Finally, our study identifies the lncRNA uc007nnj.1/miR-155-5p/Tle4 axis as a potential target for the prevention of I/R-induced retinal neuronal death.

Glaucoma is the most common cause of irreversible blindness worldwide. Elevated intraocular pressure (IOP) and relative hypoxia in the retina stimulate the production of reactive oxygen species (ROS), which, in turn, puts the retina and optic nerve under chronic oxidative stress. Emerging evidence has shown that oxidative stress can trigger PARP-1 overactivation, mitochondrial-associated endoplasmic reticulum membrane (MAM) dysregulation, and NLRP3 activation. Oxidative damage can trigger inflammasome activation, and NLRP3 is the only inflammasome associated with MAM dysregulation. In addition, multiple transcription factors are located on the MAM. This study aimed to investigate the protective effects and underlying mechanisms of a PARP-1 inhibitor (olaparib) against chronic ocular hypertension-associated retinal cell damage. We also mimicked hypoxic stimulation of a retinal precursor cell line by exposing the cells to 0.2% O2 in vitro. We discovered that chronic ocular hypertension (COH) induces oxidative damage and MAM dysregulation in the retinal ganglion cells (RGCs). The protein levels of cleaved-PARP and NLRP3 were upregulated in the retinas of the COH rats. Olaparib, a PARP-1 inhibitor, alleviated COH-induced RGC loss, retinal morphological alterations, and photopic negative response amplitude reduction. Olaparib also relieved hypoxic stimulation-induced loss of cell viability and MAM dysregulation. Additionally, some indicators of mitochondrial performance, such as reactive oxygen species accumulation, mitochondrial Ca2+ influx, and mitochondrial membrane potential collapse, decreased after olaparib treatment. Olaparib attenuated the hypoxia-induced upregulation of NLRP3 protein levels as well as the phosphorylation of ERK1/2 and histone H2A.X. These results suggest that olaparib protects RGCs from chronic intraocular pressure elevation in vivo and alleviates the abnormal MAM dysregulation and mitochondrial dysfunction caused by hypoxia in vitro. This protection may be achieved by inhibiting PARP-1 overactivation, NLRP3 upregulation, and phosphorylation of ERK1/2.

The degeneration of the optic nerve narrows the visual field, eventually causing overall vision loss. This study aimed to identify global protein changes in the retina of optic nerve crushing (ONC) mice and to identify key regulators and pathways involved in injury-induced cell death during the progression of optic neurodegeneration. Label-free quantitative proteomics combined with bioinformatic analysis was performed on retinal protein extracts from ONC and sham-operated mice. Among the 1433 proteins detected, 121 proteins were differentially expressed in the retina of ONC mice. Further bioinformatic analysis showed that various metabolic pathways, including glutamate metabolism and γ-aminobutyric acid (GABA) synthesis, were significantly dysregulated in the injured mouse retinas. Glutamate decarboxylase 1 (GAD1) is the enzyme that converts glutamate into GABA, which was significantly up-regulated during ONC injury. Exogenous GAD1 treatment increased retinal ganglion cell (RGC) survival in the ONC-injured retina. In addition, changes in GAD1 expression were also observed in several other ophthalmic diseases. Vascular endothelial growth factor B (VEGF-B) has previously been reported to protect RGCs from apoptosis and positively regulated the expression of GAD1 in the retina. Notably, combination treatment with GAD1 and VEGF-B also provided strong protection against injury-induced RGC apoptosis. These results suggest that GAD1 expression may serve as an intrinsic protective mechanism that is commonly activated during retinal injury. Targeting GAD1 may serve as a potential strategy to treat optic neurodegenerative diseases.

Traumatic optic neuropathy (TON) is a significant cause of vision loss and irreversible blindness worldwide. It is defined as retinal ganglion cell death and axon degeneration caused by injury. Optic nerve crush (ONC), a well-validated model of TON, activates retinal microglia and initiates neuroinflammation. High-mobility group box 1 (HMGB1), a non-histone chromosomal binding protein in the nucleus of eukaryotic cells, is an important inducer of microglial activation and pro-inflammatory cytokine release. The purpose of this study was to examine the protective effects and mechanism of the HMGB1 inhibitor BoxA to neuroinflammation-induced retinal ganglion cells (RGCs) damage in traumatic optic neuropathy. For that purpose, an optic nerve crush model was established in C57BL/6J mice at 10-12 weeks. Model mice received an intravitreal injection of PBS and the HMGB1 inhibitor BoxA. Our data demonstrated that HMGB1 expression increased after optic nerve crush. Retinal ganglion cell function and morphology were damaged, and retinal ganglion cell numbers were reduced after optic nerve crush. Intravitreal injection of BoxA after ONC can alleviate damage. Furthermore, BoxA reduced microglial activation and expression levels of nuclear factor κB (NF-kB), nucleotide-binding domain, leucine-rich repeat containing protein 3 (NLRP3), and apoptosis-associated speck-like protein containing a CARD (ASC) in experimental ONC mice. In summary, HMGB1 mediates NLRP3 inflammasome via NF-kB to participate in retinal inflammatory injury after ONC. Thus, intravitreal injection of BoxA has potential therapeutic benefits for the effective treatment of RGC death to prevent TON.

Purpose: Retinal ganglion cell death occurs during the glaucoma pathological process, and it is significant because of the poor regeneration capacity of retinal ganglion cells. With a constantly increasing understanding of retinal cell death mechanisms, we now know that simply blocking a specific mechanism of cell death might not prevent retinal ganglion cell death. This review aimed to summarize the mechanisms of retinal cell death in glaucoma models and discuss the caveats in restoring visual function in these studies.Methods: A literature search was done on PubMed using key words including glaucoma, ocular hypertension, retinal ganglion cell, cell death, apoptosis, necroptosis, pyroptosis, ferroptosis, autophagic cell death, and parthanatos. The literature was reviewed to summarize the information about the lethal pathways of retinal ganglion cell in the glaucoma-like animal models.Results: Based on the purpose, 100 studies were selected and discussed in this review.Conclusions: The damage to ganglion cells in glaucoma-like animals can occur via multiple lethal pathways and the molecular mechanisms are still incompletely understood. Further investigations on the crosstalk between different cell death pathways and the common upstream regulators could augment the development of novel targeting agents for the curative treatment of glaucoma.

DNA methylation is considered to play an important role in the development of diabetic retinopathy. Here, our goal was to investigate the precise role of methyl-CpG binding domain protein 2 (Mbd2) in the apoptosis of retinal ganglion cells (RGCs) in the early diabetic retina. Mbd2 was significantly upregulated after high glucose (HG) treatment and played a proapoptotic role in RGCs during HG-induced apoptosis. Combining ChIP and gene microarray datasets, the results showed that Mbd2 possessed potential binding sites for miR-345-5p, thereby elevating the expression levels of miR-345-5p via the enhancement of promoter demethylation. Activating transcription factor 1 (Atf1) played an anti-apoptotic role during the process of apoptosis in RGCs and acted as the target gene for miR-345-5p. Furthermore, the number of surviving RGCs in the diabetic retina was increased in Mbd2-knockout mice when compared with wild-type mice and the visual function became better accordingly. Collectively, our data demonstrated that the HG-induced overexpression of Mbd2 in the retina was partly responsible for the apoptosis of retinal neuronal cells through the miR-345-5p/Atf1 axis. Therefore, the targeting of Mbd2 might represent a novel therapeutic strategy for the treatment of neurodegeneration in the early diabetic retina.