{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:20:21Z","timestamp":1787026821565,"version":"build-2736575974"},"reference-count":50,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,3,22]],"date-time":"2023-03-22T00:00:00Z","timestamp":1679443200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Retinal ganglion cells (RGCs) axon loss at the site of optic nerve head (ONH) is long believed as the common pathology in glaucoma since different types of glaucoma possessing different characteristic of intraocular pressure, and this damage was only detected at the later stage.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>To address these disputes and detect early initiating events underlying RGCs, we firstly detected somatic or axonal change and compared their difference in acute and chronic phase of primary angle-closed glaucoma (PACG) patient using optical coherence tomography (OCT), then an axonal-enriched cytoskeletal protein neurofilament heavy chain and its phosphoforms (NF-H, pNF-H) were utilized to reveal spatio-temporal undetectable damage insulted by acute and chronic ocular hypertension (AOH, COH) in two well characterized glaucoma mice models.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>In clinic, we detected nonhomogeneous changes such as ONH and soma of RGCs presenting edema in acute phase but atrophy in chronic one by OCT. In AOH animal models, an increase expression of NF-H especially its phosphorylation modification was observed as early as 4 h before RGCs loss, which presented as somatic accumulation in the peripheral retina and at the sites of ONH. In contrast, in microbeads induced COH model, NF-H and pNF-H reduced significantly, these changes firstly occurred as NF-H or pNF-H disconnection at ONH and optic nerve after 2 weeks when the intraocular pressure reaching the peak; Meanwhile, we detected aqueous humor pNF-H elevation after AOH and slight reduction in the COH.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Together, our data supports that early alteration of NF-H and its phosphoforms would reveal undetectable subcellular damage consisting of peripheral somatic neurofilament compaction, impaired axonal transport and distal axonal disorganization of cytoskeleton beyond the ONH, and identifies two distinct axonal degeneration which were Wallerian combination with retrograde degeneration in acute PACG and retrograde degeneration in the chronic one.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fneur.2023.1091697","type":"journal-article","created":{"date-parts":[[2023,3,22]],"date-time":"2023-03-22T01:02:07Z","timestamp":1679446927000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":8,"title":["Alteration of neurofilament heavy chain and its phosphoforms reveals early subcellular damage beyond the optic nerve head in glaucoma"],"prefix":"10.3389","volume":"14","author":[{"given":"Lan","family":"Zhou","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongyue","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guihua","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyi","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zilin","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dingding","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huiya","family":"Fan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,3,22]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1016\/j.preteyeres.2016.12.003","article-title":"Primary angle closure glaucoma: what we know and what we don't know","volume":"57","author":"Sun","year":"2017","journal-title":"Prog Retin Eye Res."},{"key":"B2","doi-asserted-by":"publisher","first-page":"2081","DOI":"10.1016\/j.ophtha.2014.05.013","article-title":"Global prevalence of glaucoma and projections of glaucoma burden through 2040: a systematic review and meta-analysis","volume":"121","author":"Tham","year":"2014","journal-title":"Ophthalmology."},{"key":"B3","doi-asserted-by":"publisher","first-page":"2183","DOI":"10.1016\/S0140-6736(17)31469-1","article-title":"Glaucoma","volume":"390","author":"Jonas","year":"2017","journal-title":"Lancet."},{"key":"B4","doi-asserted-by":"publisher","first-page":"164","DOI":"10.1001\/jama.2020.21899","article-title":"Glaucoma in adults-screening, diagnosis, management: a review","volume":"325","author":"Stein","year":"2021","journal-title":"JAMA."},{"key":"B5","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1038\/eye.2016.295","article-title":"Assessing retinal ganglion cell damage","volume":"31","author":"Smith","year":"2017","journal-title":"Eye."},{"key":"B6","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1016\/j.molmed.2017.11.004","article-title":"Monitoring neurodegeneration in glaucoma: therapeutic implications","volume":"24","author":"Ban","year":"2018","journal-title":"Trends Mol Med."},{"key":"B7","doi-asserted-by":"publisher","first-page":"5196","DOI":"10.1073\/pnas.0913141107","article-title":"Distal axonopathy with structural persistence in glaucomatous neurodegeneration","volume":"107","author":"Crish","year":"2010","journal-title":"Proc Natl Acad Sci U S A."},{"key":"B8","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1016\/j.neuroscience.2012.10.069","article-title":"Failure of axonal transport induces a spatially coincident increase in astrocyte BDNF prior to synapse loss in a central target","volume":"229","author":"Crish","year":"2013","journal-title":"Neuroscience."},{"key":"B9","doi-asserted-by":"publisher","first-page":"201","DOI":"10.1038\/nrn1624","article-title":"Molecular motors and mechanisms of directional transport in neurons","volume":"6","author":"Hirokawa","year":"2005","journal-title":"Nat Rev Neurosci."},{"key":"B10","doi-asserted-by":"publisher","first-page":"691","DOI":"10.1038\/s41582-019-0257-2","article-title":"Axonal transport and neurological disease","volume":"15","author":"Sleigh","year":"2019","journal-title":"Nat Rev Neurol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"320","DOI":"10.1006\/exnr.2001.7818","article-title":"Intra-axonal neurofilament compaction does not evoke local axonal swelling in all traumatically injured axons","volume":"172","author":"Stone","year":"2001","journal-title":"Exp Neurol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1016\/j.jns.2005.03.015","article-title":"Neurofilament phosphoforms: surrogate markers for axonal injury, degeneration and loss","volume":"233","author":"Petzold","year":"2005","journal-title":"J Neurol Sci."},{"key":"B13","doi-asserted-by":"publisher","first-page":"1348","DOI":"10.1158\/1078-0432.CCR-14-2775","article-title":"Potential role of pNF-H, a biomarker of axonal damage in the central nervous system, as a predictive marker of chemotherapy-induced cognitive impairment","volume":"21","author":"Natori","year":"2015","journal-title":"Clin Cancer Res."},{"key":"B14","doi-asserted-by":"publisher","first-page":"324","DOI":"10.1016\/j.brainresbull.2016.07.012","article-title":"Alterations in neurofilaments and the transformation of the cytoskeleton in axons may provide insight into the aberrant neuronal changes of Alzheimer's disease","volume":"126","author":"Vickers","year":"2016","journal-title":"Brain Res Bull."},{"key":"B15","doi-asserted-by":"publisher","first-page":"241","DOI":"10.1016\/j.brainres.2004.04.023","article-title":"Alterations in neurofilament light in optic nerve in rat kainate and monkey ocular hypertension models","volume":"1013","author":"Taniguchi","year":"2004","journal-title":"Brain Res."},{"key":"B16","doi-asserted-by":"publisher","first-page":"986","DOI":"10.1167\/iovs.07-1090","article-title":"Time-dependent effects of elevated intraocular pressure on optic nerve head axonal transport and cytoskeleton proteins","volume":"49","author":"Balaratnasingam","year":"2008","journal-title":"Invest Ophthalmol Vis Sci."},{"key":"B17","doi-asserted-by":"publisher","first-page":"154","DOI":"10.1167\/iovs.02-0398","article-title":"Increase in dephosphorylation of the heavy neurofilament subunit in the monkey chronic glaucoma model","volume":"44","author":"Kashiwagi","year":"2003","journal-title":"Invest Ophthalmol Vis Sci."},{"key":"B18","doi-asserted-by":"publisher","first-page":"494","DOI":"10.3389\/fnins.2016.00494","article-title":"Early cytoskeletal protein modifications precede overt structural degeneration in the DBA\/2J mouse model of glaucoma","volume":"10","author":"Wilson","year":"2016","journal-title":"Front Neurosci."},{"key":"B19","doi-asserted-by":"publisher","first-page":"238","DOI":"10.1136\/bjo.86.2.238","article-title":"The definition and classification of glaucoma in prevalence surveys","volume":"86","author":"Foster","year":"2002","journal-title":"Br J Ophthalmol."},{"key":"B20","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1016\/j.exer.2018.12.006","article-title":"Neuronal apoptosis, axon damage and synapse loss occur synchronously in acute ocular hypertension","volume":"180","author":"Zhou","year":"2019","journal-title":"Exp Eye Res."},{"key":"B21","doi-asserted-by":"publisher","first-page":"1953","DOI":"10.3892\/etm.2017.4728","article-title":"Establishment of an experimental glaucoma animal model: a comparison of microbead injection with or without hydroxypropyl methylcellulose","volume":"14","author":"Liu","year":"2017","journal-title":"Exp Ther Med."},{"key":"B22","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1016\/j.exer.2015.06.020","article-title":"Microbead models in glaucoma","volume":"141","author":"Morgan","year":"2015","journal-title":"Exp Eye Res."},{"key":"B23","doi-asserted-by":"publisher","first-page":"470","DOI":"10.1007\/s12031-015-0707-2","article-title":"Retinal and optic nerve damage is associated with early glial responses in an experimental autoimmune glaucoma model","volume":"58","author":"Noristani","year":"2016","journal-title":"J Mol Neurosci."},{"key":"B24","doi-asserted-by":"publisher","first-page":"1975","DOI":"10.1093\/brain\/awaa098","article-title":"Neurofilaments: neurobiological foundations for biomarker applications","volume":"143","author":"Gafson","year":"2020","journal-title":"Brain."},{"key":"B25","doi-asserted-by":"publisher","first-page":"577248","DOI":"10.1016\/j.jneuroim.2020.577248","article-title":"Anti-neurofilament antibodies and neurodegeneration: markers and generators","volume":"344","author":"Zmira","year":"2020","journal-title":"J Neuroimmunol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"333","DOI":"10.1038\/sc.2010.116","article-title":"Hyperphosphorylated neurofilament NF-H as a biomarker of the efficacy of minocycline therapy for spinal cord injury","volume":"49","author":"Ueno","year":"2011","journal-title":"Spinal Cord."},{"key":"B27","first-page":"771","article-title":"Effect of intraocular pressure on rapid axoplasmic transport in monkey optic nerve","volume":"13","author":"Anderson","year":"1974","journal-title":"Invest Ophthalmol."},{"key":"B28","first-page":"426","article-title":"Orthograde and retrograde axoplasmic transport during acute ocular hypertension in the monkey","volume":"16","author":"Minckler","year":"1977","journal-title":"Invest Ophthalmol Vis Sci."},{"key":"B29","first-page":"137","article-title":"Chronic experimental glaucoma in primates. II Effect of extended intraocular pressure elevation on optic nerve head and axonal transport","volume":"19","author":"Quigley","year":"1980","journal-title":"Invest Ophthalmol Vis Sci."},{"key":"B30","doi-asserted-by":"publisher","first-page":"3632","DOI":"10.1167\/iovs.06-1002","article-title":"Axonal transport and cytoskeletal changes in the laminar regions after elevated intraocular pressure","volume":"48","author":"Balaratnasingam","year":"2007","journal-title":"Invest Ophthalmol Vis Sci."},{"key":"B31","doi-asserted-by":"publisher","first-page":"737","DOI":"10.1007\/s00401-011-0807-1","article-title":"The optic nerve head is the site of axonal transport disruption, axonal cytoskeleton damage and putative axonal regeneration failure in a rat model of glaucoma","volume":"121","author":"Chidlow","year":"2011","journal-title":"Acta Neuropathol."},{"key":"B32","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1186\/s13024-020-00400-9","article-title":"CNS axonal degeneration and transport deficits at the optic nerve head precede structural and functional loss of retinal ganglion cells in a mouse model of glaucoma","volume":"15","author":"Maddineni","year":"2020","journal-title":"Mol Neurodegener."},{"key":"B33","doi-asserted-by":"publisher","first-page":"761","DOI":"10.1097\/IJG.0000000000001598","article-title":"Comparison of peripapillary retinal nerve fiber layer thickness, functional subzones, and macular ganglion cell-inner plexiform layer in differentiating patients with mild, moderate, and severe open-angle glaucoma","volume":"29","author":"Huo","year":"2020","journal-title":"J Glaucoma."},{"key":"B34","doi-asserted-by":"publisher","first-page":"311","DOI":"10.1080\/14789450.2017.1298448","article-title":"The potential impact of recent insights into proteomic changes associated with glaucoma","volume":"14","author":"Funke","year":"2017","journal-title":"Expert Rev Proteomics."},{"key":"B35","article-title":"Alterations in molecular pathways in the retina of early experimental glaucoma eyes","author":"Cao","year":"2015","journal-title":"Int J Physiol Pathophysiol Pharmacol."},{"key":"B36","doi-asserted-by":"publisher","first-page":"a018309","DOI":"10.1101\/cshperspect.a018309","article-title":"Neurofilaments and neurofilament proteins in health and disease","volume":"9","author":"Yuan","year":"2017","journal-title":"Cold Spring Harbor Perspect Biol."},{"key":"B37","doi-asserted-by":"publisher","first-page":"577","DOI":"10.1038\/s41582-018-0058-z","article-title":"Neurofilaments as biomarkers in neurological disorders","volume":"14","author":"Khalil","year":"2018","journal-title":"Nat Rev Neurol."},{"key":"B38","doi-asserted-by":"publisher","first-page":"146","DOI":"10.3109\/21678421.2012.729596","article-title":"pNfH is a promising biomarker for ALS","volume":"14","author":"Ganesalingam","year":"2013","journal-title":"Amyotroph Lateral Scler Frontotemporal Degener."},{"key":"B39","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1016\/S0006-8993(96)00811-6","article-title":"Plaque biogenesis in brain aging and Alzheimer's disease. I Progressive changes in phosphorylation states of paired helical filaments and neurofilaments","volume":"739","author":"Su","year":"1996","journal-title":"Brain Res."},{"key":"B40","doi-asserted-by":"publisher","first-page":"463","DOI":"10.1007\/s004010050920","article-title":"Plaque biogenesis in brain aging and Alzheimer's disease. II Progressive transformation and developmental sequence of dystrophic neurites","volume":"96","author":"Su","year":"1998","journal-title":"Acta Neuropathol."},{"key":"B41","doi-asserted-by":"publisher","first-page":"1268","DOI":"10.1016\/j.bbrc.2005.08.252","article-title":"Hyperphosphorylated neurofilament NF-H is a serum biomarker of axonal injury","volume":"336","author":"Shaw","year":"2005","journal-title":"Biochem Biophys Res Commun."},{"key":"B42","doi-asserted-by":"publisher","first-page":"5785","DOI":"10.1523\/JNEUROSCI.3986-15.2016","article-title":"Tau accumulation, altered phosphorylation, and missorting promote neurodegeneration in glaucoma","volume":"36","author":"Chiasseu","year":"2016","journal-title":"J Neurosci."},{"key":"B43","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1167\/iovs.16-19103","article-title":"A review of adaptive optics optical coherence tomography: technical advances, scientific applications, and the future","volume":"57","author":"Jonnal","year":"2016","journal-title":"Invest Ophthalmol Vis Sci."},{"key":"B44","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.preteyeres.2018.08.002","article-title":"Adaptive optics imaging of the human retina","volume":"68","author":"Burns","year":"2019","journal-title":"Prog Retin Eye Res."},{"key":"B45","doi-asserted-by":"publisher","first-page":"936","DOI":"10.1080\/02713683.2016.1262043","article-title":"Cytoskeletal alteration and change of retinal nerve fiber layer birefringence in hypertensive retina","volume":"42","author":"Huang","year":"2017","journal-title":"Curr Eye Res."},{"key":"B46","doi-asserted-by":"publisher","first-page":"2118","DOI":"10.1167\/iovs.16-20553","article-title":"Reflectance spectrum and birefringence of the retinal nerve fiber layer with hypertensive damage of axonal cytoskeleton","volume":"58","author":"Huang","year":"2017","journal-title":"Invest Ophthalmol Vis Sci."},{"key":"B47","doi-asserted-by":"publisher","first-page":"868","DOI":"10.1126\/science.1068613","article-title":"Axonal self-destruction and neurodegeneration","volume":"296","author":"Raff","year":"2002","journal-title":"Science."},{"key":"B48","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1146\/annurev-neuro-060909-153248","article-title":"Wallerian degeneration, wld(s), and nmnat","volume":"33","author":"Coleman","year":"2010","journal-title":"Annu Rev Neurosci."},{"key":"B49","doi-asserted-by":"publisher","first-page":"62","DOI":"10.1016\/j.ajpath.2012.03.030","article-title":"Retrograde and wallerian axonal degeneration occur synchronously after retinal ganglion cell axotomy","volume":"181","author":"Kanamori","year":"2012","journal-title":"Am J Pathol."},{"key":"B50","doi-asserted-by":"publisher","first-page":"152","DOI":"10.1016\/j.preteyeres.2011.11.002","article-title":"The molecular basis of retinal ganglion cell death in glaucoma","volume":"31","author":"Almasieh","year":"2012","journal-title":"Prog Retin Eye Res"}],"container-title":["Frontiers in Neurology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fneur.2023.1091697\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,3,22]],"date-time":"2023-03-22T01:02:11Z","timestamp":1679446931000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fneur.2023.1091697\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,3,22]]},"references-count":50,"alternative-id":["10.3389\/fneur.2023.1091697"],"URL":"https:\/\/doi.org\/10.3389\/fneur.2023.1091697","relation":{},"ISSN":["1664-2295"],"issn-type":[{"value":"1664-2295","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,3,22]]},"article-number":"1091697"}}