{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T02:56:25Z","timestamp":1790996185024,"version":"4.1.0"},"reference-count":135,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2020,2,21]],"date-time":"2020-02-21T00:00:00Z","timestamp":1582243200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Ceramides are a family of bioactive lipids belonging to the class of sphingolipids. Sphingolipidoses are a group of inherited genetic diseases characterized by the unmetabolized sphingolipids and the consequent reduction of ceramide pool in lysosomes. Sphingolipidoses include several disorders as Sandhoff disease, Fabry disease, Gaucher disease, metachromatic leukodystrophy, Krabbe disease, Niemann Pick disease, Farber disease, and GM2 gangliosidosis. In sphingolipidosis, lysosomal lipid storage occurs in both the central nervous system and visceral tissues, and central nervous system pathology is a common hallmark for all of them. Parkinson\u2019s disease, the most common neurodegenerative movement disorder, is characterized by the accumulation and aggregation of misfolded \u03b1-synuclein that seem associated to some lysosomal disorders, in particular Gaucher disease. This review provides evidence into the role of ceramide metabolism in the pathophysiology of lysosomes, highlighting the more recent findings on its involvement in Parkinson\u2019s disease.<\/jats:p>","DOI":"10.3390\/jcm9020594","type":"journal-article","created":{"date-parts":[[2020,2,25]],"date-time":"2020-02-25T08:12:22Z","timestamp":1582618342000},"page":"594","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":43,"title":["Lysosomal Ceramide Metabolism Disorders: Implications in Parkinson\u2019s Disease"],"prefix":"10.3390","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1467-0155","authenticated-orcid":false,"given":"Silvia","family":"Paciotti","sequence":"first","affiliation":[{"name":"Laboratory of Clinical Neurochemistry, Department of Medicine, University of Perugia, Sant\u2019Andrea delle Fratte, 06132 Perugia, Italy"},{"name":"Section of Physiology and Biochemistry, Department of Experimental Medicine, University of Perugia, Sant\u2019Andrea delle Fratte, 06132 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5745-5343","authenticated-orcid":false,"given":"Elisabetta","family":"Albi","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, University of Perugia, Via Fabretti, 06123 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5722-3967","authenticated-orcid":false,"given":"Lucilla","family":"Parnetti","sequence":"additional","affiliation":[{"name":"Laboratory of Clinical Neurochemistry, Department of Medicine, University of Perugia, Sant\u2019Andrea delle Fratte, 06132 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9637-6579","authenticated-orcid":false,"given":"Tommaso","family":"Beccari","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, University of Perugia, Via Fabretti, 06123 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,2,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1007\/BF00279398","article-title":"Assignment of the gene coding for human beta-glucocerebrosidase to the region q21-q31 of chromosome 1 using monoclonal antibodies","volume":"64","author":"Barneveld","year":"1983","journal-title":"Hum. Genet."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"16862","DOI":"10.1074\/jbc.272.27.16862","article-title":"Effect of saposins A and C on the enzymatic hydrolysis of liposomal glucosylceramide","volume":"272","author":"Vaccaro","year":"1997","journal-title":"J. Biol. Chem."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1894","DOI":"10.1093\/hmg\/ddz030","article-title":"GBA haploinsufficiency accelerates alpha-synuclein pathology with altered lipid metabolism in a prodromal model of Parkinson\u2019s disease","volume":"28","author":"Ikuno","year":"2019","journal-title":"Hum. Mol. Genet."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"3432","DOI":"10.1093\/hmg\/ddw185","article-title":"Autophagic lysosome reformation dysfunction in glucocerebrosidase deficient cells: Relevance to Parkinson Disease","volume":"25","author":"Magalhaes","year":"2016","journal-title":"Hum. Mol. Genet."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"12972","DOI":"10.1074\/jbc.M802790200","article-title":"Involvement of acid \u03b2-glucosidase 1 in the salvage pathway of ceramide formation","volume":"284","author":"Kitatani","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.cytogfr.2018.04.003","article-title":"Molecular regulations and therapeutic targets of Gaucher disease","volume":"41","author":"Chen","year":"2018","journal-title":"Cytokine Growth Factor Rev."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1186\/s13024-019-0339-z","article-title":"Reduced sphingolipid hydrolase activities, substrate accumulation and ganglioside decline in Parkinson\u2019s disease","volume":"14","author":"Huebecker","year":"2019","journal-title":"Mol. Neurodegener."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Futerman, A.H., and Zimran, A. (2007). Gaucher Disease, CRC\/Taylor & Francis.","DOI":"10.1201\/9781420005509"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1093\/qjmed\/89.9.691","article-title":"Occurrence of Parkinson\u2019s syndrome in type I Gaucher disease","volume":"89","author":"Neudorfer","year":"1996","journal-title":"QJM"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1212\/01.WNL.0000072482.70963.D7","article-title":"Gaucher\u2019s disease with Parkinson\u2019s disease: Clinical and pathological aspects","volume":"61","author":"Bembi","year":"2003","journal-title":"Neurology"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1016\/S1096-7192(03)00071-4","article-title":"Gaucher disease with parkinsonian manifestations: Does glucocerebrosidase deficiency contribute to a vulnerability to parkinsonism?","volume":"79","author":"Tayebi","year":"2003","journal-title":"Mol. Genet. Metab."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1091","DOI":"10.1136\/jnnp-2019-320394","article-title":"Evolution of prodromal parkinsonian features in a cohort of GBA mutation-positive individuals: A 6-year longitudinal study","volume":"90","author":"Avenali","year":"2019","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1424","DOI":"10.1212\/WNL.0b013e3181b28601","article-title":"Mutations in GBA are associated with familial Parkinson disease susceptibility and age at onset","volume":"73","author":"Sidransky","year":"2009","journal-title":"Neurology"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1651","DOI":"10.1056\/NEJMoa0901281","article-title":"Multicenter Analysis of Glucocerebrosidase Mutations in Parkinson\u2019s Disease","volume":"361","author":"Sidransky","year":"2009","journal-title":"N. Engl. J. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.mcn.2015.03.013","article-title":"Glucocerebrosidase and Parkinson disease: Recent advances Europe PMC Funders Group","volume":"66","author":"Schapira","year":"2015","journal-title":"Mol. Cell. Neurosci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1002\/mds.27895","article-title":"The vicious cycle between \u03b1-synuclein aggregation and autophagic-lysosomal dysfunction","volume":"35","author":"Bellomo","year":"2020","journal-title":"Mov. Disord."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/j.ymgme.2011.06.008","article-title":"Aggregation of \u03b1-synuclein in brain samples from subjects with glucocerebrosidase mutations","volume":"104","author":"Choi","year":"2011","journal-title":"Mol. Genet. Metab."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1270","DOI":"10.1212\/01.wnl.0000276989.17578.02","article-title":"Mutations in the glucocerebrosidase gene are associated with early-onset Parkinson disease","volume":"69","author":"Clark","year":"2007","journal-title":"Neurology"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1093\/brain\/aws318","article-title":"Glucocerebrosidase mutations influence the natural history of Parkinson\u2019s disease in a community-based incident cohort","volume":"136","author":"Evans","year":"2013","journal-title":"Brain"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"209-e1","DOI":"10.1016\/j.neurobiolaging.2015.09.014","article-title":"Variants in GBA, SNCA, and MAPT influence Parkinson disease risk, age at onset, and progression","volume":"37","author":"Davis","year":"2016","journal-title":"Neurobiol. Aging"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"662","DOI":"10.1002\/ana.24777","article-title":"Survival and dementia in GBA-associated Parkinson\u2019s disease: The mutation matters","volume":"80","author":"Cilia","year":"2016","journal-title":"Ann. Neurol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1780","DOI":"10.1002\/mds.27199","article-title":"Cognitive impairment in Glucocerebrosidase (GBA)-associated PD: Not primarily associated with cerebrospinal fluid Abeta and Tau profiles","volume":"32","author":"Lerche","year":"2017","journal-title":"Mov. Disord."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1016\/j.ymgme.2019.10.001","article-title":"Revisiting the non-Gaucher-GBA-E326K carrier state: Is it sufficient to increase Parkinson\u2019s disease risk?","volume":"128","author":"Goldstein","year":"2019","journal-title":"Mol. Genet. Metab."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"674","DOI":"10.1002\/ana.24781","article-title":"Specifically neuropathic Gaucher\u2019s mutations accelerate cognitive decline in Parkinson\u2019s","volume":"80","author":"Liu","year":"2016","journal-title":"Ann. Neurol."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Huang, Y., Deng, L., Zhong, Y., and Yi, M. (2018). The association between E326K of GBA and the risk of Parkinson\u2019s disease. Parkinson\u2019s Dis.","DOI":"10.1155\/2018\/1048084"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.parkreldis.2016.12.014","article-title":"A \u201cdose\u201d effect of mutations in the GBA gene on Parkinson\u2019s disease phenotype","volume":"36","author":"Thaler","year":"2017","journal-title":"Parkinsonism Relat. Disord."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Simitsi, A., Koros, C., Moraitou, M., Papagiannakis, N., Antonellou, R., Bozi, M., Angelopoulou, E., Stamelou, M., Michelakakis, H., and Stefanis, L. (2018). Phenotypic Characteristics in GBA-Associated Parkinson\u2019s Disease: A Study in a Greek Population. J. Parkinson\u2019s Dis., 8.","DOI":"10.3233\/JPD-171221"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1016\/j.ymgme.2004.04.011","article-title":"Neuropathology provides clues to the pathophysiology of Gaucher disease","volume":"82","author":"Wong","year":"2004","journal-title":"Mol. Genet. Metab."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1016\/j.neuron.2017.12.012","article-title":"Reversible Conformational Conversion of \u03b1-Synuclein into Toxic Assemblies by Glucosylceramide","volume":"97","author":"Zunke","year":"2018","journal-title":"Neuron"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"9322","DOI":"10.1073\/pnas.1500937112","article-title":"Cysteine cathepsins are essential in lysosomal degradation of \u03b1-synuclein","volume":"112","author":"McGlinchey","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.cell.2011.06.001","article-title":"Gaucher disease glucocerebrosidase and \u03b1-synuclein form a bidirectional pathogenic loop in synucleinopathies","volume":"146","author":"Mazzulli","year":"2011","journal-title":"Cell"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"12101","DOI":"10.1073\/pnas.1108197108","article-title":"CNS expression of glucocerebrosidase corrects -synuclein pathology and memory in a mouse model of Gaucher-related synucleinopathy","volume":"108","author":"Sardi","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"104620","DOI":"10.1016\/j.nbd.2019.104620","article-title":"Glucocerebrosidase activity, cathepsin D and monomeric \u03b1-synuclein interactions in a stem cell derived neuronal model of a PD associated GBA1 mutation","volume":"134","author":"Yang","year":"2020","journal-title":"Neurobiol. Dis."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"7693","DOI":"10.1523\/JNEUROSCI.0628-16.2016","article-title":"Activation of \u03b2-Glucocerebrosidase Reduces Pathological \u03b1-Synuclein and Restores Lysosomal Function in Parkinson\u2019s Patient Midbrain Neurons","volume":"36","author":"Mazzulli","year":"2016","journal-title":"J. Neurosci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1007\/0-306-46826-3_33","article-title":"Ceramide as an activator lipid of cathepsin D","volume":"477","author":"Heinrich","year":"2000","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"5252","DOI":"10.1093\/emboj\/18.19.5252","article-title":"Cathepsin D targeted by acid sphingomyelinase-derived ceramide","volume":"18","author":"Heinrich","year":"1999","journal-title":"EMBO J."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1186\/1750-1172-8-140","article-title":"Unfolded protein response in Gaucher disease: From human to Drosophila","volume":"8","author":"Maor","year":"2013","journal-title":"Orphanet. J. Rare Dis."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1768","DOI":"10.1093\/hmg\/ddz005","article-title":"The effect of mutant GBA1 on accumulation and aggregation of a synuclein","volume":"28","author":"Maor","year":"2019","journal-title":"Hum. Mol. Genet."},{"key":"ref_39","first-page":"2712","article-title":"The contribution of mutant GBA to the development of Parkinson disease in Drosophila","volume":"25","author":"Maor","year":"2016","journal-title":"Hum. Mol. Genet."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1016\/j.stemcr.2016.01.013","article-title":"ER Stress and Autophagic Perturbations Lead to Elevated Extracellular \u03b1-Synuclein in GBA-N370S Parkinson\u2019s iPSC-Derived Dopamine Neurons","volume":"6","author":"Fernandes","year":"2016","journal-title":"Stem Cell Rep."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Mullin, S., Smith, L., Lee, K., D\u2019Souza, G., Woodgate, P., Elflein, J., H\u00e4llqvist, J., Toffoli, M., Streeter, A., and Hosking, J. (2020). Ambroxol for the Treatment of Patients With Parkinson Disease With and Without Glucocerebrosidase Gene Mutations: A Nonrandomized, Noncontrolled Trial. JAMA Neurol.","DOI":"10.1001\/jamaneurol.2019.4611"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1002\/ana.23614","article-title":"V Glucocerebrosidase deficiency in substantia nigra of parkinson disease brains","volume":"72","author":"Gegg","year":"2012","journal-title":"Ann. Neurol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"834","DOI":"10.1093\/brain\/awt367","article-title":"Reduced glucocerebrosidase is associated with increased \u03b1-synuclein in sporadic Parkinson\u2019s disease","volume":"137","author":"Murphy","year":"2014","journal-title":"Brain"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1344","DOI":"10.1007\/s12035-018-1090-0","article-title":"Characterization of Brain Lysosomal Activities in GBA-Related and Sporadic Parkinson\u2019s Disease and Dementia with Lewy Bodies","volume":"56","author":"Moors","year":"2018","journal-title":"Mol. Neurobiol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1423","DOI":"10.1002\/mds.27136","article-title":"Cerebrospinal fluid \u03b2-glucocerebrosidase activity is reduced in parkinson\u2019s disease patients","volume":"32","author":"Parnetti","year":"2017","journal-title":"Mov. Disord."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1019","DOI":"10.1002\/mds.25772","article-title":"Cerebrospinal fluid lysosomal enzymes and alpha-synuclein in Parkinson\u2019s disease","volume":"29","author":"Parnetti","year":"2014","journal-title":"Mov. Disord."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1186\/s13024-015-0010-2","article-title":"Selective loss of glucocerebrosidase activity in sporadic Parkinson\u2019s disease and dementia with Lewy bodies","volume":"10","author":"Chiasserini","year":"2015","journal-title":"Mol. Neurodegener."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1481","DOI":"10.1002\/mds.21399","article-title":"Lysosomal hydrolases in cerebrospinal fluid from subjects with Parkinson\u2019s disease","volume":"22","author":"Balducci","year":"2007","journal-title":"Mov. Disord."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2648","DOI":"10.1093\/brain\/awv179","article-title":"Glucocerebrosidase activity in Parkinson\u2019s disease with and without GBA mutations","volume":"138","author":"Alcalay","year":"2015","journal-title":"Brain"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.cca.2019.03.1627","article-title":"Lysosomal enzyme activities as possible CSF biomarkers of synucleinopathies","volume":"495","author":"Paciotti","year":"2019","journal-title":"Clin. Chim. Acta"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1007\/s00401-010-0741-7","article-title":"Glucocerebrosidase is present in \u03b1-synuclein inclusions in Lewy body disorders","volume":"120","author":"Stubblefield","year":"2010","journal-title":"Acta Neuropathol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"3301","DOI":"10.1093\/nar\/17.8.3301","article-title":"Nucleotide sequence of the human \u03b1-galactosidase a gene","volume":"17","author":"Kornreich","year":"1989","journal-title":"Nucleic Acids Res."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1111\/j.1365-2133.1898.tb16317.x","article-title":"CASE OF \u201cANGEIO-KERATOMA\u201d","volume":"10","author":"Anderson","year":"1898","journal-title":"Br. J. Dermatol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"129437","DOI":"10.1016\/j.bbagen.2019.129437","article-title":"Progress in the understanding and treatment of Fabry disease","volume":"1864","author":"Miller","year":"2019","journal-title":"Biochim. Biophys. Acta Gen. Subj."},{"key":"ref_55","unstructured":"Adam, M.P., Ardinger., H.H., and Pagon, R.A. (2017). Fabry Disease. Gene Reviews, University of Washington."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1016\/j.jpeds.2017.06.048","article-title":"Newborn Screening for Lysosomal Storage Disorders in Illinois: The Initial 15-Month Experience","volume":"190","author":"Burton","year":"2017","journal-title":"J. Pediatr."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1016\/j.ymgme.2016.05.015","article-title":"Pilot study of newborn screening for six lysosomal storage diseases using Tandem Mass Spectrometry","volume":"118","author":"Elliott","year":"2016","journal-title":"Mol. Genet. Metab."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1397","DOI":"10.1002\/humu.21074","article-title":"Newborn screening for Fabry disease in Taiwan reveals a high incidence of the later-onset GLA mutation c.936+919G>A (IVS4+919G>A)","volume":"30","author":"Hwu","year":"2009","journal-title":"Hum. Mutat."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1086\/504601","article-title":"High incidence of later-onset Fabry disease revealed by newborn screening","volume":"79","author":"Spada","year":"2006","journal-title":"Am. J. Hum. Genet."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1016\/j.ajpath.2014.11.004","article-title":"\u03b1-Galactosidase A knockout mice: Progressive organ pathology resembles the type 2 later-onset phenotype of fabry disease","volume":"185","author":"Bangari","year":"2015","journal-title":"Am. J. Pathol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"e39300","DOI":"10.7554\/eLife.39300","article-title":"Characterization of small fiber pathology in a mouse model of Fabry disease","volume":"7","author":"Hofmann","year":"2018","journal-title":"Elife"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"e99171","DOI":"10.1172\/jci.insight.99171","article-title":"Neuropathic pain in a Fabry disease rat model","volume":"3","author":"Miller","year":"2018","journal-title":"JCI Insight"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41598-019-45837-1","article-title":"Rats deficient in \u03b1-galactosidase A develop ocular manifestations of Fabry disease","volume":"9","author":"Miller","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1042\/BJ20130825","article-title":"A symptomatic Fabry disease mouse model generated by inducing globotriaosylceramide synthesis","volume":"456","author":"Taguchi","year":"2013","journal-title":"Biochem. J."},{"key":"ref_65","first-page":"1003","article-title":"An autopsied case of Fabry\u2019s disease presenting with parkinsonism and cardiomegaly as a cardinal clinical manifestation","volume":"34","author":"Orimo","year":"1994","journal-title":"Rinsho Shinkeigaku"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1002\/mds.20675","article-title":"Parkinsonism and Anderson Fabry\u2019s disease: A case report","volume":"21","author":"Buechner","year":"2006","journal-title":"Mov. Disord."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1016\/j.jns.2008.04.011","article-title":"Decreased activities of lysosomal acid alpha-D-galactosidase A in the leukocytes of sporadic Parkinson\u2019s disease","volume":"271","author":"Wu","year":"2008","journal-title":"J. Neurol. Sci."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1939","DOI":"10.1007\/s11064-011-0516-0","article-title":"Decreased expression of lysosomal alpha-Galactosiase a gene in sporadic parkinson\u2019s disease","volume":"36","author":"Wu","year":"2011","journal-title":"Neurochem. Res."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/j.nbd.2018.01.012","article-title":"Alpha galactosidase A activity in Parkinson\u2019s disease","volume":"112","author":"Alcalay","year":"2018","journal-title":"Neurobiol. Dis."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1016\/j.nbd.2017.11.006","article-title":"The lysosomal enzyme alpha-Galactosidase A is deficient in Parkinson\u2019s disease brain in association with the pathologic accumulation of alpha-synuclein","volume":"110","author":"Nelson","year":"2017","journal-title":"Neurobiol. Dis."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1186\/2051-5960-2-20","article-title":"Autophagy-lysosome pathway associated neuropathology and axonal degeneration in the brains of alpha-galactosidase A-deficient mice","volume":"2","author":"Nelson","year":"2014","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1042\/bj1070321","article-title":"N-Acetyl-beta-glucosaminidases in human spleen","volume":"107","author":"Robinson","year":"1968","journal-title":"Biochem. J."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1042\/bj2440801","article-title":"Intermediate forms of human beta-N-acetylhexosaminidase lack activity towards 4-methylumbelliferyl beta-N-acetylglucosaminide 6-sulphate","volume":"244","author":"Beccari","year":"1987","journal-title":"Biochem. J."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1042\/bj2520617","article-title":"Identification of beta-N-acetylhexosaminidase A in mouse tissues with the fluorigenic substrate 4-methylumbelliferyl-beta-N-acetylglucosamine 6-sulphate","volume":"252","author":"Beccari","year":"1988","journal-title":"Biochem. J."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1042\/bj2850593","article-title":"Cloning and sequence analysis of a cDNA encoding the \u03b1-subunit of mouse \u03b2-N-acetylhexosaminidase and comparison with the human enzyme","volume":"285","author":"Beccari","year":"1992","journal-title":"Biochem. J."},{"key":"ref_76","first-page":"31","article-title":"Adult GM2 gangliosidosis masquerading as slowly progressive muscular atrophy: Motor neuron disease phenotype","volume":"1","author":"Jellinger","year":"1982","journal-title":"Clin. Neuropathol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1007\/s00401-007-0264-z","article-title":"Neuronal and glial accumulation of alpha- and beta-synucleins in human lipidoses","volume":"114","author":"Suzuki","year":"2007","journal-title":"Acta Neuropathol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"3191","DOI":"10.1093\/brain\/awx285","article-title":"Excessive burden of lysosomal storage disorder gene variants in Parkinson\u2019s disease","volume":"140","author":"Robak","year":"2017","journal-title":"Brain"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1097\/00001756-200303240-00004","article-title":"Neuronal accumulation of alpha- and beta-synucleins in the brain of a GM2 gangliosidosis mouse model","volume":"14","author":"Suzuki","year":"2003","journal-title":"Neuroreport"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"5223","DOI":"10.1523\/JNEUROSCI.4860-11.2012","article-title":"Lysosomal dysfunction in a mouse model of Sandhoff disease leads to accumulation of ganglioside-bound amyloid-\u03b2 peptide","volume":"32","author":"Keilani","year":"2012","journal-title":"J. Neurosci."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1002\/mds.870090325","article-title":"Parkinsonism in adult-onset GM2 gangliosidosis","volume":"9","author":"Inzelberg","year":"1994","journal-title":"Mov. Disord."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1002\/ana.410160105","article-title":"Clinical and genetic variations in the syndrome of adult GM2 gangliosidosis resulting from hexosaminidase a deficiency","volume":"16","author":"Argov","year":"1984","journal-title":"Ann. Neurol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1481","DOI":"10.1093\/brain\/awu020","article-title":"Ambroxol improves lysosomal biochemistry in glucocerebrosidase mutation-linked Parkinson disease cells","volume":"137","author":"McNeill","year":"2014","journal-title":"Brain"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/j.parkreldis.2015.12.002","article-title":"Leukocyte glucocerebrosidase and \u03b2-hexosaminidase activity in sporadic and genetic Parkinson disease","volume":"23","author":"Kim","year":"2016","journal-title":"Park. Relat. Disord."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1073\/pnas.66.2.302","article-title":"Globoid cell leucodystrophy (Krabbe\u2019s disease): Deficiency of galactocerebroside beta-galactosidase","volume":"66","author":"Suzuki","year":"1970","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"911","DOI":"10.1358\/dof.2009.34.11.1436083","article-title":"Krabbe disease","volume":"34","author":"Sakai","year":"2009","journal-title":"Drugs Future"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1006\/mgme.2000.2990","article-title":"Krabbe disease: Genetic aspects and progress toward therapy","volume":"70","author":"Wenger","year":"2000","journal-title":"Mol. Genet. Metab."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1055\/s-0028-1091865","article-title":"Infantile globoid cell leucodystrophy (Krabbe\u2019s disease). A clinical and genetic study of 32 Swedish cases 1953\u20141967","volume":"1","author":"Hagberg","year":"1969","journal-title":"Neuropadiatrie"},{"key":"ref_89","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_90","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_91","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_92","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_93","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1002\/path.4328","article-title":"Neuronal inclusions of \u03b1-synuclein contribute to the pathogenesis of Krabbe disease","volume":"232","author":"Smith","year":"2014","journal-title":"J. Pathol."},{"key":"ref_94","doi-asserted-by":"crossref","unstructured":"Marshall, M.S., Jakubauskas, B., Bogue, W., Stoskute, M., Hauck, Z., Rue, E., Nichols, M., DiAntonio, L.L., van Breemen, R.B., and Kordower, J.H. (2018). Analysis of age-related changes in psychosine metabolism in the human brain. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0193438"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1016\/j.neulet.2014.09.041","article-title":"Increased plasma oligomeric alpha-synuclein in patients with lysosomal storage diseases","volume":"583","author":"Pchelina","year":"2014","journal-title":"Neurosci. Lett."},{"key":"ref_96","first-page":"5378284","article-title":"The Many Facets of Sphingolipids in the Specific Phases of Acute Inflammatory Response","volume":"2018","author":"Alessenko","year":"2018","journal-title":"Mediat. Inflamm."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.biochi.2017.11.011","article-title":"VDR independent induction of acid-sphingomyelinase by 1,23(OH)2 D3 in gastric cancer cells: Impact on apoptosis and cell morphology","volume":"146","author":"Albi","year":"2018","journal-title":"Biochimie"},{"key":"ref_98","doi-asserted-by":"crossref","unstructured":"Albi, E., Cataldi, S., Ceccarini, M.R., Conte, C., Ferri, I., Fettucciari, K., Patria, F.F., Beccari, T., and Codini, M. (2019). Gentamicin Targets Acid Sphingomyelinase in Cancer: The Case of the Human Gastric Cancer NCI-N87 Cells. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20184375"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"111","DOI":"10.5483\/BMBRep.2019.52.2.033","article-title":"Acid sphingomyelinase-mediated blood-brain barrier disruption in aging","volume":"52","author":"Park","year":"2019","journal-title":"BMB Rep."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/j.nbd.2014.01.010","article-title":"Ceramides and sphingomyelinases in senile plaques","volume":"65","author":"Panchal","year":"2014","journal-title":"Neurobiol. Dis."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"32","DOI":"10.33594\/000000184","article-title":"The Acid Sphingomyelinase\/ Ceramide System as Target for Ischemic Stroke Therapies","volume":"27","author":"Hagemann","year":"2019","journal-title":"Neurosignals"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"20","DOI":"10.33594\/000000183","article-title":"Pharmacological Inhibition of Acid Sphingomyelinase Ameliorates Experimental Autoimmune Encephalomyelitis","volume":"27","author":"Walter","year":"2019","journal-title":"Neurosignals"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1007\/s00401-012-1014-4","article-title":"Fingolimod attenuates ceramide-induced blood-brain barrier dysfunction in multiple sclerosis by targeting reactive astrocytes","volume":"124","author":"Nijland","year":"2012","journal-title":"Acta Neuropathol."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1111\/j.1750-3639.2011.00501.x","article-title":"Aberrant upregulation of astroglial ceramide potentiates oligodendrocyte injury","volume":"22","author":"Kim","year":"2012","journal-title":"Brain Pathol."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"3071","DOI":"10.1038\/s41598-018-21497-5","article-title":"Enhanced release of acid sphingomyelinase-enriched exosomes generates a lipidomics signature in CSF of Multiple Sclerosis patients","volume":"8","author":"Pieragostino","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_106","doi-asserted-by":"crossref","unstructured":"Sarrafpour, S., Ormseth, C., Chiang, A., Arakaki, X., Harrington, M., and Fonteh, A. (2019). Lipid Metabolism in Late-Onset Alzheimer\u2019s Disease Differs from Patients Presenting with Other Dementia Phenotypes. Int. J. Environ. Res. Public Health, 16.","DOI":"10.3390\/ijerph16111995"},{"key":"ref_107","doi-asserted-by":"crossref","unstructured":"Fonteh, A.N., Ormseth, C., Chiang, J., Cipolla, M., Arakaki, X., and Harrington, M.G. (2015). Sphingolipid metabolism correlates with cerebrospinal fluid Beta amyloid levels in Alzheimer\u2019s disease. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0125597"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"795","DOI":"10.3233\/JAD-160551","article-title":"Altered Sphingolipid Balance in Capillary Cerebral Amyloid Angiopathy","volume":"60","author":"Snkhchyan","year":"2017","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"1717","DOI":"10.1016\/B978-0-444-59565-2.00041-1","article-title":"Niemann-Pick Diseases","volume":"Volume 113","author":"Vanier","year":"2013","journal-title":"Handbook of Clinical Neurology"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1212\/01.wnl.0000194208.08904.0c","article-title":"Natural history of Type A Niemann-Pick disease: Possible endpoints for therapeutic trials","volume":"66","author":"McGovern","year":"2006","journal-title":"Neurology"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"1296","DOI":"10.1016\/j.parkreldis.2015.08.019","article-title":"SMPD1 mutations and Parkinson disease","volume":"21","author":"Dagan","year":"2015","journal-title":"Parkinsonism Relat. Disord."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"1606","DOI":"10.1212\/WNL.0b013e31828f180e","article-title":"The p.L302P mutation in the lysosomal enzyme gene SMPD1 is a risk factor for Parkinson disease","volume":"80","author":"Ozelius","year":"2013","journal-title":"Neurology"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"1294","DOI":"10.1016\/j.parkreldis.2015.08.018","article-title":"The emerging role of SMPD1 mutations in Parkinson\u2019s disease: Implications for future studies","volume":"21","author":"Alcalay","year":"2015","journal-title":"Parkinsonism Relat. Disord."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1212\/WNL.0000000000000004","article-title":"The p.L302P mutation in the lysosomal enzyme gene SMPD1 is a risk factor for Parkinson disease","volume":"82","author":"Wu","year":"2014","journal-title":"Neurology"},{"key":"ref_115","first-page":"319","article-title":"Analysis of SMPD1 gene mutations in Chinese patients with Parkinson\u2019s disease","volume":"35","author":"Song","year":"2018","journal-title":"Chin. J. Med. Genet."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/j.parkreldis.2016.10.014","article-title":"SMPD1 variants in Chinese Han patients with sporadic Parkinson\u2019s disease","volume":"34","author":"Mao","year":"2017","journal-title":"Park. Relat. Disord."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"1403","DOI":"10.1096\/fj.06-7016com","article-title":"Acid ceramidase is a novel factor required for early embryo survival","volume":"21","author":"Eliyahu","year":"2007","journal-title":"FASEB J."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"2339","DOI":"10.1096\/fj.201700585R","article-title":"Loss of acid ceramidase in myeloid cells suppresses intestinal neutrophil recruitment","volume":"32","author":"Espaillat","year":"2018","journal-title":"FASEB J."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"24695","DOI":"10.1074\/jbc.M604713200","article-title":"Acid ceramidase but not acid sphingomyelinase is required for tumor necrosis factor-\u03b1-induced PGE2 production","volume":"281","author":"Zeidan","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"830","DOI":"10.2174\/187152011797655104","article-title":"Ceramidases in Hematological Malignancies: Senseless or Neglected Target? Anticancer","volume":"11","author":"Fabrias","year":"2012","journal-title":"Agents Med. Chem."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"83208","DOI":"10.18632\/oncotarget.13079","article-title":"Acid ceramidase is upregulated in AML and represents a novel therapeutic target","volume":"7","author":"Tan","year":"2016","journal-title":"Oncotarget"},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1007\/s12272-019-01114-3","article-title":"Acid ceramidase, an emerging target for anti-cancer and anti-angiogenesis","volume":"42","author":"Cho","year":"2019","journal-title":"Arch. Pharm. Res."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.ymgme.2016.12.008","article-title":"Types A and B Niemann-Pick disease","volume":"120","author":"Schuchman","year":"2017","journal-title":"Mol. Genet. Metab."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1515\/hsz-2014-0290","article-title":"The molecular medicine of acid ceramidase","volume":"396","author":"Frohbergh","year":"2015","journal-title":"Biol. Chem."},{"key":"ref_125","first-page":"816","article-title":"Lipogranulomatosis; a new lipo-glycoprotein storage disease","volume":"24","author":"FARBER","year":"1957","journal-title":"J. Mt. Sinai Hosp. N. Y."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1186\/s13023-018-0845-z","article-title":"Acid ceramidase deficiency: Farber disease and SMA-PME","volume":"13","author":"Yu","year":"2018","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"1100","DOI":"10.1126\/science.178.4065.1100","article-title":"Ceramidase deficiency in Farber\u2019s disease (Lipogranulomatosis)","volume":"178","author":"Sugita","year":"1972","journal-title":"Science"},{"key":"ref_128","unstructured":"Adam, M.P., Ardinger, H.H., and Pagon, R.A. (2018). ASAH1-Related Disorders. Gene Reviews, University of Washington."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"1972","DOI":"10.1093\/hmg\/ddy105","article-title":"Acid ceramidase inhibition ameliorates $\u03b1$-synuclein accumulation upon loss of GBA1 function","volume":"27","author":"Kim","year":"2018","journal-title":"Hum. Mol. Genet."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1002\/humu.1380060210","article-title":"Identification of seven novel mutations associated with metachromatic leukodystrophy","volume":"6","author":"Barth","year":"1995","journal-title":"Hum. Mutat."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"1698","DOI":"10.1136\/jnnp.2005.063776","article-title":"Peripheral neuropathy in metachromatic leucodystrophy. A study of 40 cases from south India","volume":"76","author":"Bindu","year":"2005","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"1803","DOI":"10.1007\/s00415-014-7425-5","article-title":"Arylsulphatase A activity in familial parkinsonism: A pathogenetic role?","volume":"261","author":"Antelmi","year":"2014","journal-title":"Neurol."},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1111\/j.1600-0404.1994.tb01656.x","article-title":"Arylsulphatase a (ASA) activity in parkinsonism and symptomatic essential tremor","volume":"89","author":"Martinelli","year":"1994","journal-title":"Acta Neurol. Scand."},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1002\/ajmg.1320400324","article-title":"Reduced activity of arylsulfatase A and predisposition to neurological disorders: Analysis of 140 pediatric patients","volume":"40","author":"Sangiorgi","year":"1991","journal-title":"Am. J. Med. Genet."},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"2845","DOI":"10.1093\/brain\/awz205","article-title":"Arylsulfatase A, a genetic modifier of Parkinson\u2019s disease, is an \u03b1-synuclein chaperone","volume":"142","author":"Lee","year":"2019","journal-title":"Brain"}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/9\/2\/594\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T08:59:48Z","timestamp":1760173188000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/9\/2\/594"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,2,21]]},"references-count":135,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2020,2]]}},"alternative-id":["jcm9020594"],"URL":"https:\/\/doi.org\/10.3390\/jcm9020594","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,2,21]]}}}