{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T03:30:17Z","timestamp":1760239817126,"version":"build-2065373602"},"reference-count":45,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2020,12,23]],"date-time":"2020-12-23T00:00:00Z","timestamp":1608681600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Krabbe disease (KD, or globoid cell leukodystrophy; OMIM #245200) is an inherited neurodegenerative condition belonging to the class of the lysosomal storage disorders. It is caused by genetic alterations in the gene encoding for the enzyme galactosylceramidase, which is responsible for cleaving the glycosydic linkage of galatosylsphingosine (psychosine or PSY), a highly cytotoxic molecule. Here, we describe morphological and functional alterations in the visual system of the Twitcher (TWI) mouse, the most used animal model of Krabbe disease. We report in vivo electrophysiological recordings showing defective basic functional properties of the TWI primary visual cortex. In particular, we demonstrate a reduced visual acuity and contrast sensitivity, and a delayed visual response. Specific neuropathological alterations are present in the TWI visual cortex, with reduced myelination, increased astrogliosis and microglia activation, and around the whole brain. Finally, we quantify PSY content in the brain and optic nerves by high-pressure liquid chromatography-mass spectrometry methods. An increasing PSY accumulation with time, the characteristic hallmark of KD, is found in both districts. These results represent the first complete characterization of the TWI visual system. Our data set a baseline for an easy testing of potential therapies for this district, which is also dramatically affected in KD patients.<\/jats:p>","DOI":"10.3390\/biom11010007","type":"journal-article","created":{"date-parts":[[2020,12,23]],"date-time":"2020-12-23T12:19:51Z","timestamp":1608725991000},"page":"7","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Visual System Impairment in a Mouse Model of Krabbe Disease: The Twitcher Mouse"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7323-2174","authenticated-orcid":false,"given":"Ilaria","family":"Tonazzini","sequence":"first","affiliation":[{"name":"NEST, Istituto Nanoscienze-CNR and Scuola Normale Superiore, Piazza San Silvestro 12, 56127 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9930-7931","authenticated-orcid":false,"given":"Chiara","family":"Cerri","sequence":"additional","affiliation":[{"name":"Istituto Neuroscienze-CNR, Via G. Moruzzi 1, 56124 Pisa, Italy"},{"name":"Department of Pharmacy, University of Pisa, Via Bonanno Pisano 6, 56126 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1838-9064","authenticated-orcid":false,"given":"Ambra","family":"Del Grosso","sequence":"additional","affiliation":[{"name":"NEST, Istituto Nanoscienze-CNR and Scuola Normale Superiore, Piazza San Silvestro 12, 56127 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sara","family":"Antonini","sequence":"additional","affiliation":[{"name":"NEST, Istituto Nanoscienze-CNR and Scuola Normale Superiore, Piazza San Silvestro 12, 56127 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5152-8225","authenticated-orcid":false,"given":"Manuela","family":"Allegra","sequence":"additional","affiliation":[{"name":"Istituto Neuroscienze-CNR, Via G. Moruzzi 1, 56124 Pisa, Italy"},{"name":"Department of Neuroscience, Institut Pasteur, 25 Rue du Dr Roux, 75015 Paris, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4333-6378","authenticated-orcid":false,"given":"Matteo","family":"Caleo","sequence":"additional","affiliation":[{"name":"Istituto Neuroscienze-CNR, Via G. Moruzzi 1, 56124 Pisa, Italy"},{"name":"Department of Biomedical Sciences, University of Padua, Viale G. Colombo 3, 35131 Padua, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9688-2356","authenticated-orcid":false,"given":"Marco","family":"Cecchini","sequence":"additional","affiliation":[{"name":"NEST, Istituto Nanoscienze-CNR and Scuola Normale Superiore, Piazza San Silvestro 12, 56127 Pisa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,12,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1016\/j.ymgme.2019.08.001","article-title":"Rare Saposin A deficiency: Novel variant and psychosine analysis","volume":"129","author":"Calderwood","year":"2020","journal-title":"Mol. Genet. Metab."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Giussani, P., Prinetti, A., and Tringali, C. (2020). The role of Sphingolipids in myelination and myelin stability and their involvement in childhood and adult demyelinating disorders. J. Neurochem., 1\u201312.","DOI":"10.1111\/jnc.15133"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"6068","DOI":"10.1523\/JNEUROSCI.5597-08.2009","article-title":"Psychosine accumulates in membrane microdomains in the brain of Krabbe patients, disrupting the raft architecture","volume":"29","author":"White","year":"2009","journal-title":"J. Neurosci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"6068","DOI":"10.1002\/jnr.22564","article-title":"Persistence of psychosine in brain lipid rafts is a limiting factor in the therapeutic recovery of a mouse model for Krabbe disease","volume":"89","author":"White","year":"2011","journal-title":"J. Neurosci. Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1246","DOI":"10.1002\/jnr.23910","article-title":"Lithium improves cell viability in psychosine-treated MO3.13 human oligodendrocyte cell line via autophagy activation","volume":"94","author":"Antonini","year":"2016","journal-title":"J. Neurosci. Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"20097","DOI":"10.1073\/pnas.1912108116","article-title":"Genetic ablation of acid ceramidase in Krabbe disease confirms the psychosine hypothesis and identifies a new therapeutic target","volume":"116","author":"Li","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1031","DOI":"10.1002\/jnr.23753","article-title":"Synaptic failure: The achilles tendon of sphingolipidoses","volume":"94","author":"Bongarzone","year":"2016","journal-title":"J. Neurosci. Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e1529","DOI":"10.1038\/cddis.2014.483","article-title":"Role of extracellular calcium and mitochondrial oxygen species in psychosine-induced oligodendrocyte cell death","volume":"5","author":"Voccoli","year":"2014","journal-title":"Cell. Death Dis."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1002\/jbio.201500305","article-title":"RP-CARS reveals molecular spatial order anomalies in myelin of an animal model of Krabbe disease","volume":"10","author":"Cappello","year":"2017","journal-title":"J. Biophotonics"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1016\/j.gene.2014.09.046","article-title":"History, genetic, and recent advances on Krabbe disease","volume":"555","author":"Graziano","year":"2015","journal-title":"Gene"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41598-017-02998-1","article-title":"Size and specimen-dependent strategy for x-ray micro-ct and tem correlative analysis of nervous system samples","volume":"7","author":"Parlanti","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_12","unstructured":"Megha, J., and De Jesus, O. (2020, December 23). \u201cKrabbe Disease.\u201d StatPearls, Available online: https:\/\/pubmed.ncbi.nlm.nih.gov\/32965986."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"982","DOI":"10.1002\/jnr.23743","article-title":"Krabbe disease: One Hundred years from the bedside to the bench to the bedside","volume":"94","author":"Wenger","year":"2016","journal-title":"J. Neurosci. Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1136\/jnnp.26.3.195","article-title":"Diagnosis of Krabbe\u2019s infantile leucodystrophy","volume":"26","author":"Hagberg","year":"1963","journal-title":"J. Neurol. Neurosurg Psychiatry"},{"key":"ref_15","first-page":"1","article-title":"Early progression of Krabbe disease in patients with symptom onset between 0 and 5 months","volume":"14","author":"Bascou","year":"2019","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1159\/000112167","article-title":"Symptomatology of late onset krabbe\u2019s leukodystrophy: The european experience","volume":"13","author":"Lyon","year":"1991","journal-title":"Dev Neurosci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13023-018-0872-9","article-title":"A prospective natural history study of Krabbe disease in a patient cohort with onset between 6 months and 3 years of life","volume":"13","author":"Bascou","year":"2018","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1007\/s10545-012-9560-4","article-title":"Krabbe disease in adults: Phenotypic and genotypic update from a series of 11 cases and a review","volume":"36","author":"Debs","year":"2013","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1016\/0002-9394(72)90898-7","article-title":"Krabbe\u2019s disease. Histopathology and ultrastructure of the eye","volume":"74","author":"Emery","year":"1972","journal-title":"Am. J. Ophthalmol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"816","DOI":"10.1590\/S0004-282X2010000500029","article-title":"Optic nerve enlargement and leukodystrophy An unusual finding of the infantile form of Krabbe disease EspEssamEnto dE vias \u00f3ptiCas E LEuCodistrofia: Um aChado pouCo frEq\u00fcEntE da forma infantiL","volume":"68","author":"Ohlweiler","year":"2010","journal-title":"Arq. Neuropsiquiatr."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1016\/j.jaapos.2011.05.024","article-title":"Positional ocular flutter and thickened optic nerves as sentinel signs of Krabbe disease","volume":"15","author":"Brodsky","year":"2011","journal-title":"J. AAPOS"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1653","DOI":"10.1016\/j.clinph.2004.02.022","article-title":"Brain-stem auditory and visual evoked potentials in children with Krabbe disease","volume":"115","author":"Aldosari","year":"2004","journal-title":"Clin. Neurophysiol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1111\/j.1750-3639.1995.tb00601.x","article-title":"The Twitcher Mouse: A Model for Krabbe Disease and for Experimental Therapies","volume":"5","author":"Suzuki","year":"1995","journal-title":"Brain Pathol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/0166-4328(87)90007-6","article-title":"Neurological and neurobehavioral development of the mutant \u201ctwitcher\u201d mouse","volume":"25","author":"Olmstead","year":"1987","journal-title":"Behav. Brain Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1111\/j.1749-6632.1990.tb42405.x","article-title":"Myelin Pathology in the Twitcher Mouse","volume":"605","author":"Suzuki","year":"1990","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"eaax7462","DOI":"10.1126\/sciadv.aax7462","article-title":"Brain-targeted enzyme-loaded nanoparticles: A breach through the blood-brain barrier for enzyme replacement therapy in Krabbe disease","volume":"5","author":"Grosso","year":"2019","journal-title":"Sci. Adv."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"874","DOI":"10.1016\/j.ymthe.2018.01.009","article-title":"Long-Term Improvement of Neurological Signs and Metabolic Dysfunction in a Mouse Model of Krabbe\u2019s Disease after Global Gene Therapy","volume":"26","author":"Marshall","year":"2018","journal-title":"Mol. Ther."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1203\/PDR.0b013e31809fda89","article-title":"The ocular anomalies in a cystinosis animal model mimic disease pathogenesis (Pediatric Research 62, (156\u2013162))","volume":"62","author":"Kalatzis","year":"2007","journal-title":"Pediatr. Res."},{"key":"ref_29","first-page":"2212","article-title":"Quantitative in vivo and ex vivo confocal microscopy analysis of corneal cystine crystals in the Ctns -\/- knockout mouse","volume":"17","author":"Simpson","year":"2011","journal-title":"Mol. Vis."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1294","DOI":"10.1111\/j.1471-4159.2007.04525.x","article-title":"Neurochemical, morphological, and neurophysiological abnormalities in retinas of Sandhoff and GM1 gangliosidosis mice","volume":"101","author":"Denny","year":"2007","journal-title":"J. Neurochem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3389\/fcell.2020.00132","article-title":"Retinal Degeneration in MPS-IIIA Mouse Model","volume":"8","author":"Intartaglia","year":"2020","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1118","DOI":"10.1046\/j.1471-4159.1996.66031118.x","article-title":"Molecular cloning and expression of cDNA for murine galactocerebrosidase and mutation analysis of the twitcher mouse, a model of Krabbe\u2019s disease","volume":"66","author":"Sakai","year":"1996","journal-title":"J. Neurochem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1229","DOI":"10.1038\/nn.2399","article-title":"AP2\u03b3 regulates basal progenitor fate in a region- and layer-specific manner in the developing cortex","volume":"12","author":"Pinto","year":"2009","journal-title":"Nat. Neurosci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3389\/fncel.2014.00163","article-title":"Altered GABAergic markers, increased binocularity and reduced plasticity in the visual cortex of engrailed-2 knockout mice","volume":"8","author":"Allegra","year":"2014","journal-title":"Front. Cell Neurosci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1016\/j.nbd.2019.05.011","article-title":"Dysregulated autophagy as a new aspect of the molecular pathogenesis of Krabbe disease","volume":"129","author":"Angella","year":"2019","journal-title":"Neurobiol. Dis."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13229-019-0293-1","article-title":"The role of ubiquitin ligase E3A in polarized contact guidance and rescue strategies in UBE3A-deficient hippocampal neurons","volume":"10","author":"Tonazzini","year":"2019","journal-title":"Mol. Autism."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"19","DOI":"10.3921\/joptom.2009.19","article-title":"Development of visual acuity and contrast sensitivity in children","volume":"2","author":"Leat","year":"2009","journal-title":"J. Optom."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1016\/S0042-6989(98)00169-2","article-title":"Behavioural visual acuity of wild type and bcl2 transgenic mouse","volume":"39","author":"Gianfranceschi","year":"2000","journal-title":"Vis. Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"3071","DOI":"10.1016\/S0042-6989(99)00022-X","article-title":"The visual physiology of the wild type mouse determined with pattern VEPs","volume":"39","author":"Porciatti","year":"1999","journal-title":"Vis. Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/S0887-8994(99)00107-1","article-title":"Clinical and cerebral FDG PET scan in a patient with Krabbe\u2019s disease","volume":"22","author":"Bakheet","year":"2000","journal-title":"Pediatr. Neurol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"775","DOI":"10.1002\/ana.24513","article-title":"Visual evoked potentials detect cortical processing deficits in Rett syndrome","volume":"78","author":"LeBlanc","year":"2015","journal-title":"Ann. Neurol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"864","DOI":"10.1001\/archopht.1978.03910050466015","article-title":"Optic Nerve in Globoid Leukodystrophy (Krabbe\u2019s Disease)","volume":"96","author":"Brownstein","year":"1978","journal-title":"Arch. Ophthalmol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41467-020-19179-w","article-title":"Brainstem development requires galactosylceramidase and is critical for pathogenesis in a model of Krabbe disease","volume":"11","author":"Weinstock","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"4906","DOI":"10.1172\/JCI133953","article-title":"Krabbe disease successfully treated via monotherapy of intrathecal gene therapy","volume":"130","author":"Bradbury","year":"2020","journal-title":"J. Clin. Investig."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"3302","DOI":"10.1523\/JNEUROSCI.23-08-03302.2003","article-title":"Intravitreal gene therapy reduces lysosomal storage in specific areas of the CNS in mucopolysaccharidosis VII mice","volume":"23","author":"Hennig","year":"2003","journal-title":"J. Neurosci."}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/11\/1\/7\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:48:55Z","timestamp":1760179735000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/11\/1\/7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,12,23]]},"references-count":45,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,1]]}},"alternative-id":["biom11010007"],"URL":"https:\/\/doi.org\/10.3390\/biom11010007","relation":{},"ISSN":["2218-273X"],"issn-type":[{"type":"electronic","value":"2218-273X"}],"subject":[],"published":{"date-parts":[[2020,12,23]]}}}