{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T22:33:42Z","timestamp":1785537222112,"version":"3.56.0"},"reference-count":40,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2022,5,13]],"date-time":"2022-05-13T00:00:00Z","timestamp":1652400000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100004440","name":"Wellcome Trust U.K.","doi-asserted-by":"publisher","award":["WT102944"],"award-info":[{"award-number":["WT102944"]}],"id":[{"id":"10.13039\/100004440","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100004440","name":"Wellcome Trust U.K.","doi-asserted-by":"publisher","award":["UMO-2018\/30\/E\/NZ7\/00614"],"award-info":[{"award-number":["UMO-2018\/30\/E\/NZ7\/00614"]}],"id":[{"id":"10.13039\/100004440","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Huntington\u2019s disease (HD) is a fatal neurodegenerative disorder caused by a polyglutamine expansion in the huntingtin protein. HD-related pathological remodelling has been reported in HD mouse models and HD carriers. In this study, we studied structural abnormalities in the optic nerve by employing Spectral Domain Optical Coherence Tomography (SD-OCT) in pre-symptomatic HD carriers of Caucasian origin. Transmission Electron Microscopy (TEM) was used to investigate ultrastructural changes in the optic nerve of the well-established R6\/2 mouse model at the symptomatic stage of the disease. We found that pre-symptomatic HD carriers displayed a significant reduction in the retinal nerve fibre layer (RNFL) thickness, including specific quadrants: superior, inferior and temporal, but not nasal. There were no other significant irregularities in the GCC layer, at the macula level and in the optic disc morphology. The ultrastructural analysis of the optic nerve in R6\/2 mice revealed a significant thinning of the myelin sheaths, with a lamellar separation of the myelin, and a presence of myelonoid bodies. We also found a significant reduction in the thickness of myelin sheaths in peripheral nerves within the choroids area. Those ultrastructural abnormalities were also observed in HD photoreceptor cells that contained severely damaged membrane disks, with evident vacuolisation and swelling. Moreover, the outer segment of retinal layers showed a progressive disintegration. Our study explored structural changes of the optic nerve in pre- and clinical settings and opens new avenues for the potential development of biomarkers that would be of great interest in HD gene therapies.<\/jats:p>","DOI":"10.3390\/ijms23105450","type":"journal-article","created":{"date-parts":[[2022,5,13]],"date-time":"2022-05-13T08:37:02Z","timestamp":1652431022000},"page":"5450","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Structural Abnormalities of the Optic Nerve and Retina in Huntington\u2019s Disease Pre-Clinical and Clinical Settings"],"prefix":"10.3390","volume":"23","author":[{"given":"Iwona","family":"Mazur-Micha\u0142ek","sequence":"first","affiliation":[{"name":"Department of Histology and Embryology, Poznan University of Medical Sciences, 61-701 Poznan, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8972-8529","authenticated-orcid":false,"given":"Katarzyna","family":"Kowalska","sequence":"additional","affiliation":[{"name":"Department of Histology and Embryology, Poznan University of Medical Sciences, 61-701 Poznan, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Zielonka","sequence":"additional","affiliation":[{"name":"Department of Public Health, Poznan University of Medical Sciences, 61-701 Poznan, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Le\u015bniczak-Staszak","sequence":"additional","affiliation":[{"name":"Department of Histology and Embryology, Poznan University of Medical Sciences, 61-701 Poznan, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paulina","family":"Pietras","sequence":"additional","affiliation":[{"name":"Department of Histology and Embryology, Poznan University of Medical Sciences, 61-701 Poznan, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5059-268X","authenticated-orcid":false,"given":"Witold","family":"Szaflarski","sequence":"additional","affiliation":[{"name":"Department of Histology and Embryology, Poznan University of Medical Sciences, 61-701 Poznan, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Isalan","sequence":"additional","affiliation":[{"name":"Department of Life Sciences, Imperial College London, Exhibition Road, London SW7 2AZ, UK"},{"name":"Imperial College Centre for Synthetic Biology, Imperial College London, London SW7 2AZ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9874-6753","authenticated-orcid":false,"given":"Michal","family":"Mielcarek","sequence":"additional","affiliation":[{"name":"Department of Life Sciences, Imperial College London, Exhibition Road, London SW7 2AZ, UK"},{"name":"Imperial College Centre for Synthetic Biology, Imperial College London, London SW7 2AZ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,5,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1016\/S0140-6736(07)60111-1","article-title":"Huntington\u2019s disease","volume":"369","author":"Walker","year":"2007","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/j.parkreldis.2014.12.013","article-title":"Update on Huntington\u2019s disease: Advances in care and emerging therapeutic options","volume":"21","author":"Zielonka","year":"2015","journal-title":"Parkinsonism Relat. Disord."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"985","DOI":"10.1016\/0896-6273(93)90127-D","article-title":"Huntington\u2019s disease gene (IT15) is widely expressed in human and rat tissues","volume":"11","author":"Li","year":"1993","journal-title":"Neuron"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"e1058464","DOI":"10.1080\/21675511.2015.1058464","article-title":"Huntington\u2019s disease is a multi-system disorder","volume":"3","author":"Mielcarek","year":"2015","journal-title":"Rare Dis."},{"key":"ref_5","first-page":"1186","article-title":"Polyglutamine diseases: Looking beyond the neurodegenerative universe","volume":"16","author":"Mielcarek","year":"2021","journal-title":"Neural Regen. Res."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Mielcarek, M., Toczek, M., Smeets, C.J., Franklin, S.A., Bondulich, M.K., Jolinon, N., Muller, T., Ahmed, M., Dick, J.R.T., and Piotrowska, I. (2015). HDAC4-myogenin axis as an important marker of HD-related skeletal muscle atrophy. PLoS Genet., 11.","DOI":"10.1371\/journal.pgen.1005021"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1186\/s40169-015-0076-z","article-title":"A shared mechanism of muscle wasting in cancer and Huntington\u2019s disease","volume":"4","author":"Mielcarek","year":"2015","journal-title":"Clin. Transl. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"380","DOI":"10.3389\/fphys.2014.00380","article-title":"Skeletal muscle pathology in Huntington\u2019s disease","volume":"5","author":"Zielonka","year":"2014","journal-title":"Front. Physiol."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Mielcarek, M., Inuabasi, L., Bondulich, M.K., Muller, T., Osborne, G.F., Franklin, S.A., Smith, D.L., Neueder, A., Rosinski, J., and Rattray, I. (2014). Dysfunction of the CNS-heart axis in mouse models of Huntington\u2019s disease. PLoS Genet., 10.","DOI":"10.1371\/journal.pgen.1004550"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2147","DOI":"10.1016\/j.bbadis.2016.08.019","article-title":"An impaired metabolism of nucleotides underpins a novel mechanism of cardiac remodeling leading to Huntington\u2019s disease related cardiomyopathy","volume":"1862","author":"Toczek","year":"2016","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1080\/15257770.2016.1154969","article-title":"Changes in Cardiac Nucleotide Metabolism in Huntington\u2019s Disease","volume":"35","author":"Toczek","year":"2016","journal-title":"Nucleosides Nucleotides Nucleic Acids"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"910","DOI":"10.1016\/j.neuron.2016.02.003","article-title":"The Biology of Huntingtin","volume":"89","author":"Saudou","year":"2016","journal-title":"Neuron"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1016\/j.tig.2004.01.008","article-title":"Huntingtin-protein interactions and the pathogenesis of Huntington\u2019s disease","volume":"20","author":"Li","year":"2004","journal-title":"Trends Genet."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"21599","DOI":"10.1074\/jbc.M112.359307","article-title":"Proteomic analysis of wild-type and mutant huntingtin-associated proteins in mouse brains identifies unique interactions and involvement in protein synthesis","volume":"287","author":"Culver","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1080\/08164622.2021.1984179","article-title":"Retinal imaging biomarkers of neurodegenerative diseases","volume":"105","author":"Christinaki","year":"2022","journal-title":"Clin. Exp. Optom."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"3639","DOI":"10.1016\/S0042-6989(96)00169-1","article-title":"Ocular motor abnormalities in Huntington\u2019s disease","volume":"37","author":"Lasker","year":"1997","journal-title":"Vision Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"574","DOI":"10.1002\/ana.410340411","article-title":"Impairment of retinal increment thresholds in Huntington\u2019s disease","volume":"34","author":"Paulus","year":"1993","journal-title":"Ann. Neurol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1007\/s10633-018-9632-3","article-title":"Retinal dysfunction in a presymptomatic patient with Huntington\u2019s disease","volume":"136","author":"Knapp","year":"2018","journal-title":"Doc. Ophthalmol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1157","DOI":"10.1080\/00207454.2018.1489807","article-title":"Optical coherence tomography (OCT) study in Argentinean Huntington\u2019s disease patients","volume":"128","author":"Gatto","year":"2018","journal-title":"Int. J. Neurosci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2457","DOI":"10.1007\/s00415-015-7869-2","article-title":"Optical coherence tomography findings in Huntington\u2019s disease: A potential biomarker of disease progression","volume":"262","author":"Kersten","year":"2015","journal-title":"J. Neurol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/j.expneurol.2013.08.019","article-title":"Neurovascular abnormalities in humans and mice with Huntington\u2019s disease","volume":"250","author":"Lin","year":"2013","journal-title":"Exp. Neurol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"3351","DOI":"10.1093\/hmg\/11.26.3351","article-title":"Progressive retinal degeneration and dysfunction in R6 Huntington\u2019s disease mice","volume":"11","author":"Helmlinger","year":"2002","journal-title":"Hum. Mol. Genet."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"887","DOI":"10.1016\/j.nbd.2011.12.004","article-title":"Retinal dysfunction, photoreceptor protein dysregulation and neuronal remodelling in the R6\/1 mouse model of Huntington\u2019s disease","volume":"45","author":"Batcha","year":"2012","journal-title":"Neurobiol. Dis."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1016\/S0896-6273(00)80573-5","article-title":"Polyglutamine-expanded human huntingtin transgenes induce degeneration of Drosophila photoreceptor neurons","volume":"21","author":"Jackson","year":"1998","journal-title":"Neuron"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"79","DOI":"10.3389\/fmed.2020.00079","article-title":"Prevalence of Non-psychiatric Comorbidities in Pre-symptomatic and Symptomatic Huntington\u2019s Disease Gene Carriers in Poland","volume":"7","author":"Zielonka","year":"2020","journal-title":"Front. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"127","DOI":"10.3389\/fphys.2017.00127","article-title":"Transcriptional Signature of an Altered Purine Metabolism in the Skeletal Muscle of a Huntington\u2019s Disease Mouse Model","volume":"8","author":"Mielcarek","year":"2017","journal-title":"Front. Physiol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1186\/s13024-016-0128-x","article-title":"Deimmunization for gene therapy: Host matching of synthetic zinc finger constructs enables long-term mutant Huntingtin repression in mice","volume":"11","author":"Mielcarek","year":"2016","journal-title":"Mol. Neurodegener."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Mielcarek, M., Landles, C., Weiss, A., Bradaia, A., Seredenina, T., Inuabasi, L., Osborne, G.F., Wadel, K., Touller, C., and Butler, R. (2013). HDAC4 reduction: A novel therapeutic strategy to target cytoplasmic huntingtin and ameliorate neurodegeneration. PLoS Biol., 11.","DOI":"10.1371\/journal.pbio.1001717"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1016\/S0092-8674(00)81369-0","article-title":"Exon 1 of the HD gene with an expanded CAG repeat is sufficient to cause a progressive neurological phenotype in transgenic mice","volume":"87","author":"Mangiarini","year":"1996","journal-title":"Cell"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1016\/j.neuron.2012.10.002","article-title":"The neuronal organization of the retina","volume":"76","author":"Masland","year":"2012","journal-title":"Neuron"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Moffitt, H., McPhail, G.D., Woodman, B., Hobbs, C., and Bates, G.P. (2009). Formation of polyglutamine inclusions in a wide range of non-CNS tissues in the HdhQ150 knock-in mouse model of Huntington\u2019s disease. PLoS ONE, 4.","DOI":"10.1371\/journal.pone.0008025"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1827","DOI":"10.1007\/s00417-017-3715-9","article-title":"OCT in Alzheimer\u2019s disease: Thinning of the RNFL and superior hemiretina","volume":"255","author":"Cunha","year":"2017","journal-title":"Graefes Arch. Clin. Exp. Ophthalmol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1097\/WNO.0b013e3182701745","article-title":"Retinal nerve fiber layer thickness in Parkinson disease","volume":"33","author":"Kirbas","year":"2013","journal-title":"J. Neuroophthalmol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"832768","DOI":"10.3389\/fnagi.2022.832768","article-title":"Retinal Nerve Fiber Layer Thickness and Associations With Cognitive Impairment in Parkinson\u2019s Disease","volume":"14","author":"Chang","year":"2022","journal-title":"Front. Aging Neurosci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"915","DOI":"10.3390\/tomography7040076","article-title":"Longitudinal Assessment Using Optical Coherence Tomography in Patients with Friedreich\u2019s Ataxia","volume":"7","author":"Plapp","year":"2021","journal-title":"Tomography"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"108","DOI":"10.3109\/01658107.2011.580898","article-title":"Retinal Nerve Fibre Layer and Macular Thinning in Spinocerebellar Ataxia and Cerebellar Multisystem Atrophy","volume":"35","author":"Pula","year":"2011","journal-title":"Neuroophthalmology"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"559","DOI":"10.3389\/fphys.2018.00559","article-title":"Neuro-Cardio Mechanisms in Huntington\u2019s Disease and Other Neurodegenerative Disorders","volume":"9","author":"Critchley","year":"2018","journal-title":"Front. Physiol."},{"key":"ref_38","first-page":"2547","article-title":"Cardiac dysfunction in Huntington\u2019s Disease","volume":"20","author":"Zielonka","year":"2014","journal-title":"Exp. Clin. Cardiol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1093\/brain\/awn269","article-title":"Visual system involvement in patients with Friedreich\u2019s ataxia","volume":"132","author":"Fortuna","year":"2009","journal-title":"Brain"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1016\/S0896-6273(02)01190-X","article-title":"SCA7 knockin mice model human SCA7 and reveal gradual accumulation of mutant ataxin-7 in neurons and abnormalities in short-term plasticity","volume":"37","author":"Yoo","year":"2003","journal-title":"Neuron"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/10\/5450\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:10:19Z","timestamp":1760137819000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/10\/5450"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,5,13]]},"references-count":40,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2022,5]]}},"alternative-id":["ijms23105450"],"URL":"https:\/\/doi.org\/10.3390\/ijms23105450","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,5,13]]}}}