Abstract
Traumatic optic neuropathy or other neurodegenerative diseases, including optic nerve transection, glaucoma, and diabetic retinopathy, can lead to progressive and irreversible visual damage. Long non-coding RNAs (lncRNAs), which belong to the family of non-protein-coding transcripts, have been linked to the pathogenesis, progression, and prognosis of these lesions. Retinal ganglion cells (RGCs) are critical for the transmission of visual information to the brain, damage to which results in visual loss. Apoptosis has been identified as one of the most essential modes of RGC death. Emerging evidence suggests that lncRNAs can regulate RGC degeneration by directly or indirectly modulating apoptosis-associated signaling pathways. This review presents a comprehensive overview of the role of lncRNAs in RGC apoptosis at transcriptional, post-transcriptional, translational, and post-translational levels, emphasizing on the potential mechanisms of action. The current limitations and future perspectives of exploring the connection between lncRNAs and RGC apoptosis have been summarized. Understanding the intricate molecular interaction network of lncRNAs and RGC apoptosis will open new avenues for the identification of novel diagnostic biomarkers, therapeutic targets, and molecules for prognostic evaluation of diseases related to RGC injury.
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Al Hussein Al Awamlh S, Wareham LK, Risner ML, Calkins DJ (2021) Insulin signaling as a therapeutic target in glaucomatous neurodegeneration. Int J Mol Sci. https://doi.org/10.3390/ijms22094672
Ali T, Grote P (2020) Beyond the RNA-dependent function of LncRNA genes. Elife. https://doi.org/10.7554/eLife.60583
Almasieh M, Wilson AM, Morquette B, Cueva Vargas JL, Di Polo A (2012) The molecular basis of retinal ganglion cell death in glaucoma. Prog Retin Eye Res 31:152–181. https://doi.org/10.1016/j.preteyeres.2011.11.002
Ayupe AC, Beckedorff F, Levay K et al (2021) Identification of long noncoding RNAs in injury-resilient and injury-susceptible mouse retinal ganglion cells. BMC Genom 22:741. https://doi.org/10.1186/s12864-021-08050-x
Bao H, Sun D, Qi P, Jiang S (2019) Astragaloside protects oxygen and glucose deprivation induced injury by regulation of microRNA-21 in retinal ganglion cell line RGC-5. Biomed Pharmacother 109:1826–1833. https://doi.org/10.1016/j.biopha.2018.11.024
Beermann J, Piccoli MT, Viereck J, Thum T (2016) Non-coding RNAs in development and disease: background, mechanisms, and therapeutic approaches. Physiol Rev 96:1297–1325. https://doi.org/10.1152/physrev.00041.2015
Bhan A, Mandal SS (2014) Long noncoding RNAs: emerging stars in gene regulation, epigenetics and human disease. ChemMedChem 9:1932–1956. https://doi.org/10.1002/cmdc.201300534
Bridges MC, Daulagala AC, Kourtidis A (2021) LNCcation: lncRNA localization and function. J Cell Biol. https://doi.org/10.1083/jcb.202009045
Buckley NJ, Johnson R, Zuccato C, Bithell A, Cattaneo E (2010) The role of REST in transcriptional and epigenetic dysregulation in Huntington’s disease. Neurobiol Dis 39:28–39. https://doi.org/10.1016/j.nbd.2010.02.003
Burdon KP, Crawford A, Casson RJ et al (2012) Glaucoma risk alleles at CDKN2B-AS1 are associated with lower intraocular pressure, normal-tension glaucoma, and advanced glaucoma. Ophthalmology 119:1539–1545. https://doi.org/10.1016/j.ophtha.2012.02.004
Cai LJ, Tu L, Huang XM et al (2020) LncRNA MALAT1 facilitates inflammasome activation via epigenetic suppression of Nrf2 in Parkinson’s disease. Mol Brain 13:130. https://doi.org/10.1186/s13041-020-00656-8
Chen HY, Ho YJ, Chou HC et al (2020) TGF-β1 signaling protects retinal ganglion cells from oxidative stress via modulation of the HO-1/Nrf2 pathway. Chem Biol Interact 331:109249. https://doi.org/10.1016/j.cbi.2020.109249
Chitranshi N, Dheer Y, Abbasi M et al (2018) Glaucoma pathogenesis and neurotrophins: focus on the molecular and genetic basis for therapeutic prospects. Curr Neuropharmacol 16:1018–1035. https://doi.org/10.2174/1570159x16666180419121247
Choong CJ, Baba K, Mochizuki H (2016) Gene therapy for neurological disorders. Expert Opin Biol Ther 16:143–159. https://doi.org/10.1517/14712598.2016.1114096
Cissé Y, Bai L, Meng T (2018) LncRNAs in genetic basis of glaucoma. BMJ Open Ophthalmol 3:e000131. https://doi.org/10.1136/bmjophth-2017-000131
Delás MJ, Sabin LR, Dolzhenko E et al (2017) lncRNA requirements for mouse acute myeloid leukemia and normal differentiation. Elife. https://doi.org/10.7554/eLife.25607
Djebali S, Davis CA, Merkel A et al (2012) Landscape of transcription in human cells. Nature 489:101–108. https://doi.org/10.1038/nature11233
Dykes IM, Emanueli C (2017) Transcriptional and post-transcriptional gene regulation by long non-coding RNA. Genom Proteomics Bioinform 15:177–186. https://doi.org/10.1016/j.gpb.2016.12.005
Fão L, Mota SI, Rego AC (2019) Sha** the Nrf2-ARE-related pathways in Alzheimer’s and Parkinson’s diseases. Ageing Res Rev 54:100942. https://doi.org/10.1016/j.arr.2019.100942
Fricker M, Tolkovsky AM, Borutaite V, Coleman M, Brown GC (2018) Neuronal cell death. Physiol Rev 98:813–880. https://doi.org/10.1152/physrev.00011.2017
Gao S, Jakobs TC (2016) Mice homozygous for a deletion in the glaucoma susceptibility locus INK4 show increased vulnerability of retinal ganglion cells to elevated intraocular pressure. Am J Pathol 186:985–1005. https://doi.org/10.1016/j.ajpath.2015.11.026
Ge Y, Zhang R, Feng Y, Li H (2020) Mbd2 mediates retinal cell apoptosis by targeting the lncRNA Mbd2-AL1/miR-188-3p/Traf3 axis in Ischemia/reperfusion injury. Mol Ther Nucleic Acids 19:1250–1265. https://doi.org/10.1016/j.omtn.2020.01.011
Gharahkhani P, Burdon KP, Fogarty R et al (2014) Common variants near ABCA1, AFAP1 and GMDS confer risk of primary open-angle glaucoma. Nat Genet 46:1120–1125. https://doi.org/10.1038/ng.3079
Gong W, Li J, Zhu G et al (2019) Chlorogenic acid relieved oxidative stress injury in retinal ganglion cells through IncRNA-TUG1/Nrf2. Cell Cycle 18:1549–1559. https://doi.org/10.1080/15384101.2019.1612697
Graf J, Kretz M (2020) From structure to function: route to understanding lncRNA mechanism. BioEssays 42:e2000027. https://doi.org/10.1002/bies.202000027
Haneklaus M, O’Neill LA (2015) NLRP3 at the interface of metabolism and inflammation. Immunol Rev 265:53–62. https://doi.org/10.1111/imr.12285
Ip JY, Nakagawa S (2012) Long non-coding RNAs in nuclear bodies. Dev Growth Differ 54:44–54. https://doi.org/10.1111/j.1440-169X.2011.01303.x
Jiang Q, Shan K, Qun-Wang X et al (2016) Long non-coding RNA-MIAT promotes neurovascular remodeling in the eye and brain. Oncotarget 7:49688–49698. https://doi.org/10.18632/oncotarget.10434
Johnson WM, Aboobakar IF, Finnegan L et al (2017) Identification of the hnRNPL and LOXL1-AS1 lncRNA complex: Implications for pathology in exfoliation glaucoma. Investig Ophthalmol Vis Sci 58:5590
Kim TK, Hemberg M, Gray JM et al (2010) Widespread transcription at neuronal activity-regulated enhancers. Nature 465:182–187. https://doi.org/10.1038/nature09033
Kopp F, Mendell JT (2018) Functional classification and experimental dissection of long noncoding RNAs. Cell 172:393–407. https://doi.org/10.1016/j.cell.2018.01.011
Leung RK, Whittaker PA (2005) RNA interference: from gene silencing to gene-specific therapeutics. Pharmacol Ther 107:222–239. https://doi.org/10.1016/j.pharmthera.2005.03.004
Li CP, Wang SH, Wang WQ, Song SG, Liu XM (2017a) Long noncoding RNA-Sox2OT knockdown alleviates diabetes mellitus-induced retinal ganglion cell (RGC) injury. Cell Mol Neurobiol 37:361–369. https://doi.org/10.1007/s10571-016-0380-1
Li Y, ** L, Dong A, Zhou X, Yuan H (2017b) Microarray expression profile analysis of long non-coding RNAs in optineurin E50K mutant transgenic mice. Mol Med Rep 16:1255–1261. https://doi.org/10.3892/mmr.2017.6722
Liao Y, Tang L (2016) Inducible RNAi system and its application in novel therapeutics. Crit Rev Biotechnol 36:630–638. https://doi.org/10.3109/07388551.2014.1003030
Lin MT, Beal MF (2006) Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 443:787–795. https://doi.org/10.1038/nature05292
Liu H, Xu D, Zhong X et al (2019) LncRNA-mRNA competing endogenous RNA network depicts transcriptional regulation in ischaemia reperfusion injury. J Cell Mol Med 23:2272–2276. https://doi.org/10.1111/jcmm.14163
Liu YF, Huang S, Ng TK et al (2020) Longitudinal evaluation of immediate inflammatory responses after intravitreal AAV2 injection in rats by optical coherence tomography. Exp Eye Res 193:107955. https://doi.org/10.1016/j.exer.2020.107955
Lu Y, Brommer B, Tian X et al (2020) Reprogramming to recover youthful epigenetic information and restore vision. Nature 588:124–129. https://doi.org/10.1038/s41586-020-2975-4
Maes ME, Schlamp CL, Nickells RW (2017) BAX to basics: how the BCL2 gene family controls the death of retinal ganglion cells. Prog Retin Eye Res 57:1–25. https://doi.org/10.1016/j.preteyeres.2017.01.002
Memczak S, Jens M, Elefsinioti A et al (2013) Circular RNAs are a large class of animal RNAs with regulatory potency. Nature 495:333–338. https://doi.org/10.1038/nature11928
Moazzeni H, Khani M, Elahi E (2020) Insights into the regulatory molecules involved in glaucoma pathogenesis. Am J Med Genet C Semin Med Genet 184:782–827. https://doi.org/10.1002/ajmg.c.31833
Nie XG, Fan DS, Huang YX et al (2018) Downregulation of microRNA-149 in retinal ganglion cells suppresses apoptosis through activation of the PI3K/Akt signaling pathway in mice with glaucoma. Am J Physiol Cell Physiol 315:C839-c849. https://doi.org/10.1152/ajpcell.00324.2017
Panni S, Lovering RC, Porras P, Orchard S (2020) Non-coding RNA regulatory networks. Biochim Biophys Acta Gene Regul Mech 1863:194417. https://doi.org/10.1016/j.bbagrm.2019.194417
Ponting CP, Oliver PL, Reik W (2009) Evolution and functions of long noncoding RNAs. Cell 136:629–641. https://doi.org/10.1016/j.cell.2009.02.006
Qian X, Zhao J, Yeung PY, Zhang QC, Kwok CK (2019) Revealing lncRNA structures and interactions by sequencing-based approaches. Trends Biochem Sci 44:33–52. https://doi.org/10.1016/j.tibs.2018.09.012
Quinn JJ, Chang HY (2016) Unique features of long non-coding RNA biogenesis and function. Nat Rev Genet 17:47–62. https://doi.org/10.1038/nrg.2015.10
Rosenson RS, Brewer HB Jr, Ansell BJ et al (2016) Dysfunctional HDL and atherosclerotic cardiovascular disease. Nat Rev Cardiol 13:48–60. https://doi.org/10.1038/nrcardio.2015.124
Ross AG, McDougald DS, Khan RS et al (2021) Rescue of retinal ganglion cells in optic nerve injury using cell-selective AAV mediated delivery of SIRT1. Gene Ther 28:256–264. https://doi.org/10.1038/s41434-021-00219-z
Simion V, Zhou H, Haemmig S et al (2020) A macrophage-specific lncRNA regulates apoptosis and atherosclerosis by tethering HuR in the nucleus. Nat Commun 11:6135. https://doi.org/10.1038/s41467-020-19664-2
Simpson EM, Korecki AJ, Fornes O et al (2019) New MiniPromoter Ple345 (NEFL) drives strong and specific expression in retinal ganglion cells of mouse and primate retina. Hum Gene Ther 30:257–272. https://doi.org/10.1089/hum.2018.118
Sirey TM, Roberts K, Haerty W et al (2019) The long non-coding RNA Cerox1 is a post transcriptional regulator of mitochondrial complex I catalytic activity. Elife. https://doi.org/10.7554/eLife.45051
Skol AD, Jung SC, Sokovic AM et al (2020) Integration of genomics and transcriptomics predicts diabetic retinopathy susceptibility genes. Elife. https://doi.org/10.7554/eLife.59980
St Laurent G, Wahlestedt C, Kapranov P (2015) The Landscape of long noncoding RNA classification. Trends Genet 31:239–251. https://doi.org/10.1016/j.tig.2015.03.007
Statello L, Guo CJ, Chen LL, Huarte M (2021) Gene regulation by long non-coding RNAs and its biological functions. Nat Rev Mol Cell Biol 22:96–118. https://doi.org/10.1038/s41580-020-00315-9
Sun KD, Wang JQ, Zhang QL (2019) LncRNA MEG3 promotes glaucomatous retinal ganglion cell apoptosis via upregulating miR-106 target gene caspase-8. Clin Surg Res Commun 3:08–18. https://doi.org/10.31491/csrc.2019.09.002
Suzuki A, Guerrini MM, Yamamoto K (2021) Functional genomics of autoimmune diseases. Ann Rheum Dis. https://doi.org/10.1136/annrheumdis-2019-216794
Syc-Mazurek SB, Libby RT (2019) Axon injury signaling and compartmentalized injury response in glaucoma. Prog Retin Eye Res 73:100769. https://doi.org/10.1016/j.preteyeres.2019.07.002
Tan YT, Lin JF, Li T et al (2021) LncRNA-mediated posttranslational modifications and reprogramming of energy metabolism in cancer. Cancer Commun 41:109–120. https://doi.org/10.1002/cac2.12108
Tang R, Wang YC, Mei X et al (2020) LncRNA GAS5 attenuates fibroblast activation through inhibiting Smad3 signaling. Am J Physiol Cell Physiol 319:C105-c115. https://doi.org/10.1152/ajpcell.00059.2020
Thomas CN, Berry M, Logan A, Blanch RJ, Ahmed Z (2017) Caspases in retinal ganglion cell death and axon regeneration. Cell Death Discov 3:17032. https://doi.org/10.1038/cddiscovery.2017.32
Ulitsky I (2016) Evolution to the rescue: using comparative genomics to understand long non-coding RNAs. Nat Rev Genet 17:601–614. https://doi.org/10.1038/nrg.2016.85
Van Bergen NJ, Wood JP, Chidlow G et al (2009) Recharacterization of the RGC-5 retinal ganglion cell line. Investig Ophthalmol Vis Sci 50:4267–4272. https://doi.org/10.1167/iovs.09-3484
van Wyk M, Hulliger EC, Girod L, Ebneter A, Kleinlogel S (2017) Present molecular limitations of ON-bipolar cell targeted gene therapy. Front Neurosci 11:161. https://doi.org/10.3389/fnins.2017.00161
Wan P, Su W, Zhuo Y (2017) The role of long noncoding RNAs in neurodegenerative diseases. Mol Neurobiol 54:2012–2021. https://doi.org/10.1007/s12035-016-9793-6
Wan P, Su W, Zhang Y et al (2020) LncRNA H19 initiates microglial pyroptosis and neuronal death in retinal ischemia/reperfusion injury. Cell Death Differ 27:176–191. https://doi.org/10.1038/s41418-019-0351-4
Wang KC, Chang HY (2011) Molecular mechanisms of long noncoding RNAs. Mol Cell 43:904–914. https://doi.org/10.1016/j.molcel.2011.08.018
Wang JX, Zhang XJ, Li Q et al (2015) MicroRNA-103/107 regulate programmed necrosis and myocardial ischemia/reperfusion injury through targeting FADD. Circ Res 117:352–363. https://doi.org/10.1161/circresaha.117.305781
Wang M, Li J, Zheng Y (2020) The potential role of nuclear factor erythroid 2-related factor 2 (Nrf2) in glaucoma: a review. Med Sci Monit 26:e921514. https://doi.org/10.12659/msm.921514
Wang L, Gong J, Wang J, Dan J, Wang P (2021a) Long non-coding RNA MALAT1 alleviates the elevated intraocular pressure (eiop)-induced glaucoma progression via sponging miR-149-5p. Curr Eye Res 46:903–911. https://doi.org/10.1080/02713683.2020.1843686
Wang Z, Chen X, Liu N et al (2021b) A nuclear long non-coding RNA LINC00618 accelerates ferroptosis in a manner dependent upon apoptosis. Mol Ther 29:263–274. https://doi.org/10.1016/j.ymthe.2020.09.024
Wiggs JL, Pasquale LR (2017) Genetics of glaucoma. Hum Mol Genet 26:R21-r27. https://doi.org/10.1093/hmg/ddx184
Wiggs JL, Yaspan BL, Hauser MA et al (2012) Common variants at 9p21 and 8q22 are associated with increased susceptibility to optic nerve degeneration in glaucoma. PLoS Genet 8:e1002654. https://doi.org/10.1371/journal.pgen.1002654
Williams PR, Benowitz LI, Goldberg JL, He Z (2020) Axon regeneration in the mammalian optic nerve. Annu Rev Vis Sci 6:195–213. https://doi.org/10.1146/annurev-vision-022720-094953
Wu X, Liu Y, Ji Y (2021) Carboxymethylated chitosan alleviated oxidative stress injury in retinal ganglion cells via IncRNA-THOR/IGF2BP1 axis. Genes Genom 43:643–651. https://doi.org/10.1007/s13258-021-01085-0
**a X, Yu CY, Bian M et al (2020) MEF2 transcription factors differentially contribute to retinal ganglion cell loss after optic nerve injury. PLoS ONE 15:e0242884. https://doi.org/10.1371/journal.pone.0242884
**e L, Jiang B, Mao M (2017) Expression profiling of extracellular long noncoding RNAs and message RNAs in aqueous humor of glaucoma patients. Investig Ophthalmol Vis Sci 58:185
**e L, Mao M, Wang C et al (2019) Potential biomarkers for primary open-angle glaucoma identified by long noncoding RNA profiling in the aqueous humor. Am J Pathol 189:739–752. https://doi.org/10.1016/j.ajpath.2018.12.011
Xu Y, **ng YQ (2018) Long non-coding RNA GAS5 contributed to the development of glaucoma via regulating the TGF-beta signaling pathway. Eur Rev Med Pharmacol Sci 22:896–902
Xu L, Zhang Z, **e T, Zhang X, Dai T (2016) Inhibition of BDNF-AS provides neuroprotection for retinal ganglion cells against ischemic injury. PLoS ONE 11:e0164941. https://doi.org/10.1371/journal.pone.0164941
Xu Y, Wang X, Zhang Y (2019) Myocardial infarction-related transcripts (MIAT) participate in diabetic optic nerve injury by regulating heart shock protein 5 (HSPA5) via competitively binding to MicroRNA-379. Med Sci Monit 25:2096–2103. https://doi.org/10.12659/MSM.911930
Yan K, Niu L, Tian H, Su F, Chen Y (2021) Long noncoding RNA maternally expressed gene 3 targets miR-30b and regulates the AKT serine/threonine kinase 1/phosphoinositide 3-kinase signaling pathway of H2O2-induced proliferation, apoptosis, and oxidative stress in retinal ganglion cells. J Biomater Tissue Eng 11:351–358. https://doi.org/10.1166/jbt.2021.2412
Yang N, Yang J, He X, Zhang W, **ng Y (2021a) Construction and analysis of mRNA, lncRNA, and transcription factor regulatory networks after retinal ganglion cell injury. Exp Eye Res 215:108915. https://doi.org/10.1016/j.exer.2021.108915
Yang S, Yang H, Luo Y et al (2021b) Long non-coding RNAs in neurodegenerative diseases. Neurochem Int 148:105096. https://doi.org/10.1016/j.neuint.2021.105096
Yao J, Wang XQ, Li YJ et al (2016) Long non-coding RNA MALAT1 regulates retinal neurodegeneration through CREB signaling. EMBO Mol Med 8:346–362. https://doi.org/10.15252/emmm.201505725
Zhang K, Shi ZM, Chang YN et al (2014) The ways of action of long non-coding RNAs in cytoplasm and nucleus. Gene 547:1–9. https://doi.org/10.1016/j.gene.2014.06.043
Zhang L, Liang D, Chen C et al (2018) Circular siRNAs for reducing off-target effects and enhancing long-term gene silencing in cells and mice. Mol Ther Nucleic Acids 10:237–244. https://doi.org/10.1016/j.omtn.2017.12.007
Zhang L, Dong Y, Wang Y et al (2019) Long non-coding RNAs in ocular diseases: new and potential therapeutic targets. FEBS J 286:2261–2272. https://doi.org/10.1111/febs.14827
Zhang F, Zhao Y, Cao M et al (2021a) The potential role of long noncoding RNAs in primary open-angle glaucoma. Graefes Arch Clin Exp Ophthalmol 259:3805–3814. https://doi.org/10.1007/s00417-021-05279-w
Zhang R, Feng Y, Lu J, Ge Y, Li H (2021b) lncRNA Ttc3-209 promotes the apoptosis of retinal ganglion cells in retinal ischemia reperfusion injury by targeting the miR-484/Wnt8a axis. Investig Ophthalmol Vis Sci 62:13. https://doi.org/10.1167/iovs.62.3.13
Zheng M, Zheng Y, Gao M et al (2020) Expression and clinical value of lncRNA MALAT1 and lncRNA ANRIL in glaucoma patients. Exp Ther Med 19:1329–1335. https://doi.org/10.3892/etm.2019.8345
Zhou RR, Li HB, You QS et al (2019) Silencing of GAS5 alleviates glaucoma in rat models by reducing retinal ganglion cell apoptosis. Hum Gene Ther 30:1505–1519. https://doi.org/10.1089/hum.2019.056
Zhou M, Lu B, Tan W, Fu M (2020) Identification of lncRNA-miRNA-mRNA regulatory network associated with primary open angle glaucoma. BMC Ophthalmol. https://doi.org/10.1186/s12886-020-01365-5
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This work was supported by the Provincial Natural Science Foundation of Hubei Province (grant number 2020CFB240) and the Fundamental Research Funds for the Central Universities (grant number 2042020kf0065).
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This work was supported by the Provincial Natural Science Foundation of Hubei Province (Grant Number 2020CFB240) and the Fundamental Research Funds for the Central Universities (Grant Number 2042020kf0065).
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NZ and NY conceived and initiated this review. NZ wrote the first draft of this manuscript. WC and XH collected and archived the related literature. YX, and NY revised, formatted, and edited the manuscript. All authors read and approved the final version of the manuscript for publication.
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Zhang, N., Cao, W., He, X. et al. Long Non-Coding RNAs in Retinal Ganglion Cell Apoptosis. Cell Mol Neurobiol 43, 561–574 (2023). https://doi.org/10.1007/s10571-022-01210-x
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DOI: https://doi.org/10.1007/s10571-022-01210-x