Background Optic neuropathy is a major cause of irreversible blindness,yet the molecular determinants that contribute to neuronal demise have not been fully elucidated.Several studies have identified'ephrin signal...Background Optic neuropathy is a major cause of irreversible blindness,yet the molecular determinants that contribute to neuronal demise have not been fully elucidated.Several studies have identified'ephrin signaling'as one of the most dysregulated pathways in the early pathophysiology of optic neuropathy with varied etiologies.Developmentally,gradients in ephrin signaling coordinate retinotopic mapping via repulsive modulation of cytoskeletal dynamics in neuronal membranes.Little is known about the role ephrin signaling plays in the postnatal visual system and its correlation with the onset of optic neuropathy.Methods Postnatal mouse retinas were collected for mass spectrometry analysis for erythropoietin-producing human hepatocellular(Eph)receptors.Optic nerve crush(ONC)model was employed to induce optic neuropathy,and proteomic changes during the acute phase of neuropathic onset were analyzed.Confocal and super-resolution microscopy determined the cellular localization of activated Eph receptors after ONC injury.Eph receptor inhibitors assessed the neuroprotective effect of ephrin signaling modulation.Results Mass spectrometry revealed expression of seven Eph receptors(EphA2,A4,A5,B1,B2,B3,and B6)in postnatal mouse retinal tissue.Immunoblotting analysis indicated a significant increase in phosphorylation of these Eph receptors 48 h after ONC.Confocal microscopy demonstrated the presence of both subclasses of Eph receptors within the retina.Stochastic optical reconstruction microscopy(STORM)super-resolution imaging combined with optimal transport colocalization analysis revealed a significant colocalization of activated Eph receptors with injured neuronal cells,compared to uninjured neuronal and/or injured glial cells,48 h post-ONC.Eph receptor inhibitors displayed notable neuroprotective effects for retinal ganglion cells(RGCs)after six days of ONC injury.Conclusions Our findings demonstrate the functional presence of diverse Eph receptors in the postnatal mammalian retina,capable of modulating multiple biological processes.Pan-Eph receptor activation contributes to the onset of neuropathy in optic neuropathies,with preferential activation of Eph receptors on neuronal processes in the inner retina following optic nerve injury.Notably,Eph receptor activation precedes neuronal loss.We observed a neuroprotective effect on RGCs upon inhibiting Eph receptors.Our study highlights the importance of investigating this repulsive pathway in early optic neuropathies and provides a comprehensive characterization of the receptors present in the developed retina of mice,relevant to both homeostasis and disease processes.展开更多
Retinal ganglion cells,a crucial component of the central nervous system,are often affected by irreversible visual impairment due to various conditions,including trauma,tumors,ischemia,and glaucoma.Studies have shown ...Retinal ganglion cells,a crucial component of the central nervous system,are often affected by irreversible visual impairment due to various conditions,including trauma,tumors,ischemia,and glaucoma.Studies have shown that the optic nerve crush model and glaucoma model are commonly used to study retinal ganglion cell injury.While these models differ in their mechanisms,both ultimately result in retinal ganglion cell injury.With advancements in high-throughput technologies,techniques such as microarray analysis,RNA sequencing,and single-cell RNA sequencing have been widely applied to characterize the transcriptomic profiles of retinal ganglion cell injury,revealing underlying molecular mechanisms.This review focuses on optic nerve crush and glaucoma models,elucidating the mechanisms of optic nerve injury and neuron degeneration induced by glaucoma through single-cell transcriptomics,transcriptome analysis,and chip analysis.Research using the optic nerve crush model has shown that different retinal ganglion cell subtypes exhibit varying survival and regenerative capacities following injury.Single-cell RNA sequencing has identified multiple genes associated with retinal ganglion cell protection and regeneration,such as Gal,Ucn,and Anxa2.In glaucoma models,high-throughput sequencing has revealed transcriptomic changes in retinal ganglion cells under elevated intraocular pressure,identifying genes related to immune response,oxidative stress,and apoptosis.These genes are significantly upregulated early after optic nerve injury and may play key roles in neuroprotection and axon regeneration.Additionally,CRISPR-Cas9 screening and ATAC-seq analysis have identified key transcription factors that regulate retinal ganglion cell survival and axon regeneration,offering new potential targets for neurorepair strategies in glaucoma.In summary,single-cell transcriptomic technologies provide unprecedented insights into the molecular mechanisms underlying optic nerve injury,aiding in the identification of novel therapeutic targets.Future researchers should integrate advanced single-cell sequencing with multi-omics approaches to investigate cell-specific responses in retinal ganglion cell injury and regeneration.Furthermore,computational models and systems biology methods could help predict molecular pathways interactions,providing valuable guidance for clinical research on optic nerve regeneration and repair.展开更多
Dear Editor,Traumatic optic neuropathy(TON)is a severe vision-threatening condition,with an incidence rate ranging from 0.7% to 2.5%[1].The limited regenerative capacity of the optic nerve and the challenges of nerve ...Dear Editor,Traumatic optic neuropathy(TON)is a severe vision-threatening condition,with an incidence rate ranging from 0.7% to 2.5%[1].The limited regenerative capacity of the optic nerve and the challenges of nerve transplantation result in substantial and irreversible visual loss in patients with TON.展开更多
AIM:To investigate the effects of adenosine triphosphate(ATP)and melatonin,which have antioxidant and antiinflammatory activities,on potential 5-fluorouracil(5-FU)-induced optic nerve damage in rats.METHODS:Twenty-fou...AIM:To investigate the effects of adenosine triphosphate(ATP)and melatonin,which have antioxidant and antiinflammatory activities,on potential 5-fluorouracil(5-FU)-induced optic nerve damage in rats.METHODS:Twenty-four rats were categorized into four groups of six rats:healthy(HG),5-FU(FUG),ATP+5-FU(AFU),and melatonin+5-FU(MFU).ATP(4 mg/kg)and melatonin(10 mg/kg)were administered intraperitoneally and orally,respectively.One hour after ATP and melatonin administration,rats in the AFU,MFU,and FUG were intraperitoneally injected with 5-FU(100 mg/kg).ATP and melatonin were administered once daily for 10d.5-FU was administered at a single dose on days 1,3,and 5 of the experiment.After 10d,the rats were euthanized and optic nerve tissues were extracted.Optic nerve tissues were biochemically and histopathologically examined.RESULTS:ATP and melatonin treatments inhibited the increase in malondialdehyde(MDA)and interleukin-6(IL-6)levels,which were elevated in the FUG.The treatments also prevented the decrease in total glutathione(tGSH)levels and the superoxide dismutase(SOD)and catalase(CAT)activities(P<0.001).This inhibition was higher in the ATP group than in the melatonin group(P<0.001).ATP prevented histopathological damage better than melatonin(P<0.05).CONCLUSION:ATP and melatonin have the potential to be used in alleviating 5-FU-induced optic nerve damage.In addition,ATP treatment shows better protective effects than melatonin.展开更多
AIM:To detect and segregate causative mutations in congenital families with optic nerve hypoplasia(ONH).M E T H O D S:Two unrel a ted consanguineous Pakistani families with severe ONH,showing features of micropthalmia...AIM:To detect and segregate causative mutations in congenital families with optic nerve hypoplasia(ONH).M E T H O D S:Two unrel a ted consanguineous Pakistani families with severe ONH,showing features of micropthalmia,nystagmus,corneal opacity,and keratopathy were included.Genetic analysis was carried out by Target Panel Sequencing,and the nucleotide variant was confirmed by Sanger sequencing.In silico analyses were carried out to study the protein order-disorder functions and their effects on messenger ribonucleic acid(mRNA).RESULTS:Target panel sequencing revealed that the afflicted family members carried a novel frameshift mutation(NM_145178.4;c.91del G;p.Gly31Glyfs*55)that ensued in the conservation of an amino acid residue in the bHLH domain of ATOH7 protein.In silico studies predicted that the activity of the ATOH7 gene is probably affected by this mutation,which results in a shortened and nonfunctional protein.Three-dimensional structural analysis shows that DNA binding may be impacted by amino acid changes from non-polar to positively charged and vice versa(Arg42Pro and Pro18Arg),as well as from positively charged(Arg)to a small polar amino acid(Gly).CONCLUSION:A novel ATOH7 mutation is harmful.This study also emphasizes the potential effects of modified ATOH7 configurations on the stability and functionality of proteins.展开更多
基金supported in part by a generous philanthropic gift from Dr.Nasser Ibrahim Al-Rashid to the Bascom Palmer Eye Institute,and an Alcon Research Institute Young Investigator Grant(DP)supported by NlH Center Core Grant P30EY01801a Research to Prevent Blindness Unrestricted Grant(New York,NY,USA).
文摘Background Optic neuropathy is a major cause of irreversible blindness,yet the molecular determinants that contribute to neuronal demise have not been fully elucidated.Several studies have identified'ephrin signaling'as one of the most dysregulated pathways in the early pathophysiology of optic neuropathy with varied etiologies.Developmentally,gradients in ephrin signaling coordinate retinotopic mapping via repulsive modulation of cytoskeletal dynamics in neuronal membranes.Little is known about the role ephrin signaling plays in the postnatal visual system and its correlation with the onset of optic neuropathy.Methods Postnatal mouse retinas were collected for mass spectrometry analysis for erythropoietin-producing human hepatocellular(Eph)receptors.Optic nerve crush(ONC)model was employed to induce optic neuropathy,and proteomic changes during the acute phase of neuropathic onset were analyzed.Confocal and super-resolution microscopy determined the cellular localization of activated Eph receptors after ONC injury.Eph receptor inhibitors assessed the neuroprotective effect of ephrin signaling modulation.Results Mass spectrometry revealed expression of seven Eph receptors(EphA2,A4,A5,B1,B2,B3,and B6)in postnatal mouse retinal tissue.Immunoblotting analysis indicated a significant increase in phosphorylation of these Eph receptors 48 h after ONC.Confocal microscopy demonstrated the presence of both subclasses of Eph receptors within the retina.Stochastic optical reconstruction microscopy(STORM)super-resolution imaging combined with optimal transport colocalization analysis revealed a significant colocalization of activated Eph receptors with injured neuronal cells,compared to uninjured neuronal and/or injured glial cells,48 h post-ONC.Eph receptor inhibitors displayed notable neuroprotective effects for retinal ganglion cells(RGCs)after six days of ONC injury.Conclusions Our findings demonstrate the functional presence of diverse Eph receptors in the postnatal mammalian retina,capable of modulating multiple biological processes.Pan-Eph receptor activation contributes to the onset of neuropathy in optic neuropathies,with preferential activation of Eph receptors on neuronal processes in the inner retina following optic nerve injury.Notably,Eph receptor activation precedes neuronal loss.We observed a neuroprotective effect on RGCs upon inhibiting Eph receptors.Our study highlights the importance of investigating this repulsive pathway in early optic neuropathies and provides a comprehensive characterization of the receptors present in the developed retina of mice,relevant to both homeostasis and disease processes.
基金supported by the National Natural Science Foundation of China,Nos.82471123,82171053the Jilin Province Special Project for Talent in Medical and Health Sciences,No.2024WSXK-E01the Natural Science Foundation of Jilin Province,YDZJ202501ZYTS318(all to GL).
文摘Retinal ganglion cells,a crucial component of the central nervous system,are often affected by irreversible visual impairment due to various conditions,including trauma,tumors,ischemia,and glaucoma.Studies have shown that the optic nerve crush model and glaucoma model are commonly used to study retinal ganglion cell injury.While these models differ in their mechanisms,both ultimately result in retinal ganglion cell injury.With advancements in high-throughput technologies,techniques such as microarray analysis,RNA sequencing,and single-cell RNA sequencing have been widely applied to characterize the transcriptomic profiles of retinal ganglion cell injury,revealing underlying molecular mechanisms.This review focuses on optic nerve crush and glaucoma models,elucidating the mechanisms of optic nerve injury and neuron degeneration induced by glaucoma through single-cell transcriptomics,transcriptome analysis,and chip analysis.Research using the optic nerve crush model has shown that different retinal ganglion cell subtypes exhibit varying survival and regenerative capacities following injury.Single-cell RNA sequencing has identified multiple genes associated with retinal ganglion cell protection and regeneration,such as Gal,Ucn,and Anxa2.In glaucoma models,high-throughput sequencing has revealed transcriptomic changes in retinal ganglion cells under elevated intraocular pressure,identifying genes related to immune response,oxidative stress,and apoptosis.These genes are significantly upregulated early after optic nerve injury and may play key roles in neuroprotection and axon regeneration.Additionally,CRISPR-Cas9 screening and ATAC-seq analysis have identified key transcription factors that regulate retinal ganglion cell survival and axon regeneration,offering new potential targets for neurorepair strategies in glaucoma.In summary,single-cell transcriptomic technologies provide unprecedented insights into the molecular mechanisms underlying optic nerve injury,aiding in the identification of novel therapeutic targets.Future researchers should integrate advanced single-cell sequencing with multi-omics approaches to investigate cell-specific responses in retinal ganglion cell injury and regeneration.Furthermore,computational models and systems biology methods could help predict molecular pathways interactions,providing valuable guidance for clinical research on optic nerve regeneration and repair.
基金supported by Guangzhou Key Projects of Brain Science and Brain-Like Intelligence Technology(20200730009)the National Natural Science Foundation of China(81870656)the Natural Science Foundation of Guangdong Province of China(2017A030313610 and 2023A1515012397).
文摘Dear Editor,Traumatic optic neuropathy(TON)is a severe vision-threatening condition,with an incidence rate ranging from 0.7% to 2.5%[1].The limited regenerative capacity of the optic nerve and the challenges of nerve transplantation result in substantial and irreversible visual loss in patients with TON.
文摘AIM:To investigate the effects of adenosine triphosphate(ATP)and melatonin,which have antioxidant and antiinflammatory activities,on potential 5-fluorouracil(5-FU)-induced optic nerve damage in rats.METHODS:Twenty-four rats were categorized into four groups of six rats:healthy(HG),5-FU(FUG),ATP+5-FU(AFU),and melatonin+5-FU(MFU).ATP(4 mg/kg)and melatonin(10 mg/kg)were administered intraperitoneally and orally,respectively.One hour after ATP and melatonin administration,rats in the AFU,MFU,and FUG were intraperitoneally injected with 5-FU(100 mg/kg).ATP and melatonin were administered once daily for 10d.5-FU was administered at a single dose on days 1,3,and 5 of the experiment.After 10d,the rats were euthanized and optic nerve tissues were extracted.Optic nerve tissues were biochemically and histopathologically examined.RESULTS:ATP and melatonin treatments inhibited the increase in malondialdehyde(MDA)and interleukin-6(IL-6)levels,which were elevated in the FUG.The treatments also prevented the decrease in total glutathione(tGSH)levels and the superoxide dismutase(SOD)and catalase(CAT)activities(P<0.001).This inhibition was higher in the ATP group than in the melatonin group(P<0.001).ATP prevented histopathological damage better than melatonin(P<0.05).CONCLUSION:ATP and melatonin have the potential to be used in alleviating 5-FU-induced optic nerve damage.In addition,ATP treatment shows better protective effects than melatonin.
文摘AIM:To detect and segregate causative mutations in congenital families with optic nerve hypoplasia(ONH).M E T H O D S:Two unrel a ted consanguineous Pakistani families with severe ONH,showing features of micropthalmia,nystagmus,corneal opacity,and keratopathy were included.Genetic analysis was carried out by Target Panel Sequencing,and the nucleotide variant was confirmed by Sanger sequencing.In silico analyses were carried out to study the protein order-disorder functions and their effects on messenger ribonucleic acid(mRNA).RESULTS:Target panel sequencing revealed that the afflicted family members carried a novel frameshift mutation(NM_145178.4;c.91del G;p.Gly31Glyfs*55)that ensued in the conservation of an amino acid residue in the bHLH domain of ATOH7 protein.In silico studies predicted that the activity of the ATOH7 gene is probably affected by this mutation,which results in a shortened and nonfunctional protein.Three-dimensional structural analysis shows that DNA binding may be impacted by amino acid changes from non-polar to positively charged and vice versa(Arg42Pro and Pro18Arg),as well as from positively charged(Arg)to a small polar amino acid(Gly).CONCLUSION:A novel ATOH7 mutation is harmful.This study also emphasizes the potential effects of modified ATOH7 configurations on the stability and functionality of proteins.
