{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T14:16:29Z","timestamp":1790691389920,"version":"4.1.0"},"reference-count":99,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2020,2,26]],"date-time":"2020-02-26T00:00:00Z","timestamp":1582675200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Cyprus Institute of Neurology and Genetics","award":["Telethon grant 33173135"],"award-info":[{"award-number":["Telethon grant 33173135"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The ASAH1 gene encodes acid ceramidase (AC), an enzyme that is implicated in the metabolism of ceramide (Cer). Mutations in the ASAH1 gene cause two different disorders, Farber disease (FD), a rare lysosomal storage disorder, and a rare form of spinal muscular atrophy combined with progressive myoclonic epilepsy (SMA-PME). In the absence of human in vitro neuronal disease models and to gain mechanistic insights into pathological effects of ASAH1 deficiency, we established and characterized a stable ASAH1 knockdown (ASAH1KD) SH-SY5Y cell line. ASAH1KD cells displayed reduced proliferation due to elevated apoptosis and G1\/S cell cycle arrest. Distribution of LAMP1-positive lysosomes towards the cell periphery and significantly shortened and less branched neurites upon differentiation, implicate AC for lysosome positioning and neuronal development, respectively. Lipidomic analysis revealed changes in the intracellular levels of distinct sphingolipid species, importantly without Cer accumulation, in line with altered gene transcription within the sphingolipid pathway. Additionally, the transcript levels for Rho GTPases (RhoA, Rac1, and Cdc42), which are key regulators of axonal orientation, neurite branching and lysosome positioning were found to be dysregulated. This study shows the critical role of AC in neurons and suggests how AC depletion leads to defects seen in neuropathology of SMA-PME and FD.<\/jats:p>","DOI":"10.3390\/ijms21051607","type":"journal-article","created":{"date-parts":[[2020,2,27]],"date-time":"2020-02-27T03:21:16Z","timestamp":1582773676000},"page":"1607","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Acid Ceramidase Depletion Impairs Neuronal Survival and Induces Morphological Defects in Neurites Associated with Altered Gene Transcription and Sphingolipid Content"],"prefix":"10.3390","volume":"21","author":[{"given":"Kalia","family":"Kyriakou","sequence":"first","affiliation":[{"name":"Cyprus School of Molecular Medicine, P.O. Box 23462, 1683 Nicosia, Cyprus"},{"name":"Biochemical Genetics Department, The Cyprus Institute of Neurology and Genetics, P.O. Box 23462, 1683 Nicosia, Cyprus"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3920-9584","authenticated-orcid":false,"given":"Carsten","family":"W. Lederer","sequence":"additional","affiliation":[{"name":"Cyprus School of Molecular Medicine, P.O. Box 23462, 1683 Nicosia, Cyprus"},{"name":"Molecular Genetics Thalassaemia Department, The Cyprus Institute of Neurology and Genetics, P.O. Box 23462, 1683 Nicosia, Cyprus"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina","family":"Kleanthous","sequence":"additional","affiliation":[{"name":"Cyprus School of Molecular Medicine, P.O. Box 23462, 1683 Nicosia, Cyprus"},{"name":"Molecular Genetics Thalassaemia Department, The Cyprus Institute of Neurology and Genetics, P.O. Box 23462, 1683 Nicosia, Cyprus"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthi","family":"Drousiotou","sequence":"additional","affiliation":[{"name":"Cyprus School of Molecular Medicine, P.O. Box 23462, 1683 Nicosia, Cyprus"},{"name":"Biochemical Genetics Department, The Cyprus Institute of Neurology and Genetics, P.O. Box 23462, 1683 Nicosia, Cyprus"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Malekkou","sequence":"additional","affiliation":[{"name":"Cyprus School of Molecular Medicine, P.O. Box 23462, 1683 Nicosia, Cyprus"},{"name":"Biochemical Genetics Department, The Cyprus Institute of Neurology and Genetics, P.O. Box 23462, 1683 Nicosia, Cyprus"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,2,26]]},"reference":[{"key":"ref_1","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_2","doi-asserted-by":"crossref","first-page":"2133","DOI":"10.1016\/j.bbamem.2006.08.019","article-title":"Acid ceramidase and human disease","volume":"1758","author":"Park","year":"2006","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1016\/j.ajhg.2012.05.001","article-title":"Spinal muscular atrophy associated with progressive myoclonic epilepsy is caused by mutations in ASAH1","volume":"91","author":"Zhou","year":"2012","journal-title":"Am. J. Hum. Genet."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1578","DOI":"10.1038\/ejhg.2016.28","article-title":"ASAH1 variant causing a mild SMA phenotype with no myoclonic epilepsy: A clinical, biochemical and molecular study","volume":"24","author":"Filosto","year":"2016","journal-title":"Eur. J. Hum. Genet. EJHG"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1006\/geno.2002.6686","article-title":"Insertional mutagenesis of the mouse acid ceramidase gene leads to early embryonic lethality in homozygotes and progressive lipid storage disease in heterozygotes","volume":"79","author":"Li","year":"2002","journal-title":"Genomics"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"3489","DOI":"10.1111\/j.1460-9568.2004.03852.x","article-title":"Elevation of the level and activity of acid ceramidase in Alzheimer\u2019s disease brain","volume":"20","author":"Huang","year":"2004","journal-title":"Eur. J. Neurosci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"864","DOI":"10.1016\/j.ajpath.2016.12.005","article-title":"Acid Ceramidase Deficiency in Mice Results in a Broad Range of Central Nervous System Abnormalities","volume":"187","author":"Sikora","year":"2017","journal-title":"Am. J. Pathol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"800","DOI":"10.1038\/381800a0","article-title":"Suppression of ceramide-mediated programmed cell death by sphingosine-1-phosphate","volume":"381","author":"Cuvillier","year":"1996","journal-title":"Nature"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1038\/365557a0","article-title":"Sphingosine-1-phosphate as second messenger in cell proliferation induced by PDGF and FCS mitogens","volume":"365","author":"Olivera","year":"1993","journal-title":"Nature"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1016\/j.jns.2008.12.010","article-title":"Ceramide and neurodegeneration: Susceptibility of neurons and oligodendrocytes to cell damage and death","volume":"278","author":"Jana","year":"2009","journal-title":"J. Neurol. Sci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2929","DOI":"10.1523\/JNEUROSCI.17-09-02929.1997","article-title":"Distinct roles for ceramide and glucosylceramide at different stages of neuronal growth","volume":"17","author":"Schwarz","year":"1997","journal-title":"J. Neurosci. Off. J. Soc. Neurosci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"14476","DOI":"10.1016\/S0021-9258(19)85263-8","article-title":"Inhibition of sphingolipid synthesis affects axonal outgrowth in cultured hippocampal neurons","volume":"268","author":"Harel","year":"1993","journal-title":"J. Biol. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"10990","DOI":"10.1074\/jbc.270.18.10990","article-title":"A regulatory role for sphingolipids in neuronal growth. Inhibition of sphingolipid synthesis and degradation have opposite effects on axonal branching","volume":"270","author":"Schwarz","year":"1995","journal-title":"J. Biol. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1551","DOI":"10.1046\/j.1471-4159.1995.65041551.x","article-title":"Sphingolipid biosynthesis is necessary for dendrite growth and survival of cerebellar Purkinje cells in culture","volume":"65","author":"Furuya","year":"1995","journal-title":"J. Neurochem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"8199","DOI":"10.1523\/JNEUROSCI.19-19-08199.1999","article-title":"Ceramide signaling downstream of the p75 neurotrophin receptor mediates the effects of nerve growth factor on outgrowth of cultured hippocampal neurons","volume":"19","author":"Brann","year":"1999","journal-title":"J. Neurosci. Off. J. Soc. Neurosci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1046\/j.1471-4159.1998.71010366.x","article-title":"Ceramide and its interconvertible metabolite sphingosine function as indispensable lipid factors involved in survival and dendritic differentiation of cerebellar Purkinje cells","volume":"71","author":"Furuya","year":"1998","journal-title":"J. Neurochem."},{"key":"ref_17","first-page":"1814","article-title":"Phosphatidylcholine synthesis is elevated in neuronal models of Gaucher disease due to direct activation of CTP:phosphocholine cytidylyltransferase by glucosylceramide","volume":"16","author":"Bodennec","year":"2002","journal-title":"FASEB J. Off. Publ. Fed. Am. Soc. Exp. Biol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1046\/j.1365-2990.2003.00455.x","article-title":"Reduced rates of axonal and dendritic growth in embryonic hippocampal neurones cultured from a mouse model of Sandhoff disease","volume":"29","author":"Pelled","year":"2003","journal-title":"Neuropathol. Appl. Neurobiol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1007\/978-1-62703-640-5_2","article-title":"Considerations for the use of SH-SY5Y neuroblastoma cells in neurobiology","volume":"1078","author":"Kovalevich","year":"2013","journal-title":"Methods Mol. Biol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1038\/ncb2204","article-title":"Lysosomal positioning coordinates cellular nutrient responses","volume":"13","author":"Korolchuk","year":"2011","journal-title":"Nat. Cell Biol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1126\/science.279.5350.509","article-title":"Rho GTPases and the actin cytoskeleton","volume":"279","author":"Hall","year":"1998","journal-title":"Science"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1270","DOI":"10.1126\/science.7652575","article-title":"An essential role for Rho, Rac, and Cdc42 GTPases in cell cycle progression through G1","volume":"269","author":"Olson","year":"1995","journal-title":"Science"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"314","DOI":"10.3389\/fncel.2014.00314","article-title":"Rho family GTPases: Key players in neuronal development, neuronal survival, and neurodegeneration","volume":"8","author":"Stankiewicz","year":"2014","journal-title":"Front. Cell. Neurosci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1023\/A:1021702812146","article-title":"A role for small GTPase RhoA in regulating intracellular membrane traffic of lysosomes in invasive rat hepatoma cells","volume":"34","author":"Nishimura","year":"2002","journal-title":"Histochem. J."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1007\/s004410000243","article-title":"Small guanosine triphosphatase Rho\/Rho-associated kinase as a novel regulator of intracellular redistribution of lysosomes in invasive tumor cells","volume":"301","author":"Nishimura","year":"2000","journal-title":"Cell Tissue Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1016\/j.ajhg.2012.11.021","article-title":"Loss of function of glucocerebrosidase GBA2 is responsible for motor neuron defects in hereditary spastic paraplegia","volume":"92","author":"Martin","year":"2013","journal-title":"Am. J. Hum. Genet."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"9429","DOI":"10.1093\/nar\/gks716","article-title":"The histone demethylase PHF8 is essential for cytoskeleton dynamics","volume":"40","author":"Gallego","year":"2012","journal-title":"Nucleic Acids Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1002\/ana.20886","article-title":"Alsin\/Rac1 signaling controls survival and growth of spinal motoneurons","volume":"60","author":"Jacquier","year":"2006","journal-title":"Ann. Neurol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1007\/s12031-007-0024-5","article-title":"Smn depletion alters profilin II expression and leads to upregulation of the RhoA\/ROCK pathway and defects in neuronal integrity","volume":"32","author":"Bowerman","year":"2007","journal-title":"J. Mol. Neurosci. MN"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"4865","DOI":"10.1093\/hmg\/ddr425","article-title":"The spinal muscular atrophy disease protein SMN is linked to the Rho-kinase pathway via profilin","volume":"20","author":"Nolle","year":"2011","journal-title":"Hum. Mol. Genet."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1159","DOI":"10.1016\/S0092-8674(05)80020-0","article-title":"The Rho family GTPases RhoA, Rac1, and CDC42Hs regulate transcriptional activation by SRF","volume":"81","author":"Hill","year":"1995","journal-title":"Cell"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"690","DOI":"10.1038\/nrm2476","article-title":"Mammalian Rho GTPases: New insights into their functions from in vivo studies","volume":"9","author":"Heasman","year":"2008","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"657","DOI":"10.2741\/2710","article-title":"Diverse roles of Rho family GTPases in neuronal development, survival, and death","volume":"13","author":"Linseman","year":"2008","journal-title":"Front. Biosci. A J. Virtual Libr."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1002\/jnr.20415","article-title":"p21-Activated kinase-1 is necessary for depolarization-mediated neuronal survival","volume":"79","author":"Johnson","year":"2005","journal-title":"J. Neurosci. Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"957","DOI":"10.1111\/j.1471-4159.2006.03802.x","article-title":"Rho family GTPase inhibition reveals opposing effects of mitogen-activated protein kinase kinase\/extracellular signal-regulated kinase and Janus kinase\/signal transducer and activator of transcription signaling cascades on neuronal survival","volume":"97","author":"Loucks","year":"2006","journal-title":"J. Neurochem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1080\/08977190600560651","article-title":"Rho GTPases and cell cycle control","volume":"24","author":"Villalonga","year":"2006","journal-title":"Growth Factors"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"3003","DOI":"10.4161\/cc.21088","article-title":"Cell cycle regulation of Rho signaling pathways","volume":"11","author":"David","year":"2012","journal-title":"Cell Cycle"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1002\/emmm.201302781","article-title":"Farber disease: Understanding a fatal childhood disorder and dissecting ceramide biology","volume":"5","author":"Sands","year":"2013","journal-title":"EMBO Mol. Med."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"4329","DOI":"10.1242\/jcs.196287","article-title":"Mechanisms and functions of lysosome positioning","volume":"129","author":"Pu","year":"2016","journal-title":"J. Cell Sci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.ceb.2017.01.008","article-title":"Moving and positioning the endolysosomal system","volume":"47","author":"Bonifacino","year":"2017","journal-title":"Curr. Opin. Cell Biol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1111\/tra.12587","article-title":"Mechanisms of lysosomal positioning and movement","volume":"19","author":"Cabukusta","year":"2018","journal-title":"Traffic"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1016\/j.cell.2016.05.078","article-title":"An ER-Associated Pathway Defines Endosomal Architecture for Controlled Cargo Transport","volume":"166","author":"Jongsma","year":"2016","journal-title":"Cell"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2233","DOI":"10.1016\/j.cub.2016.06.046","article-title":"Endolysosomes Are the Principal Intracellular Sites of Acid Hydrolase Activity","volume":"26","author":"Bright","year":"2016","journal-title":"Curr. Biol. CB"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1007\/BF03033750","article-title":"Overexpression of ROCK in human breast cancer cells: Evidence that ROCK activity mediates intracellular membrane traffic of lysosomes","volume":"9","author":"Nishimura","year":"2003","journal-title":"Pathol. Oncol. Res. POR"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1995","DOI":"10.1038\/onc.2012.292","article-title":"Cancer-associated lysosomal changes: Friends or foes?","volume":"32","author":"Kallunki","year":"2013","journal-title":"Oncogene"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1007\/978-1-4939-6934-0_19","article-title":"Lysosomal Biology in Cancer","volume":"1594","author":"Fennelly","year":"2017","journal-title":"Methods Mol. Biol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"C481","DOI":"10.1152\/ajpcell.00150.2019","article-title":"Control of lysosomal TRPML1 channel activity and exosome release by acid ceramidase in mouse podocytes","volume":"317","author":"Li","year":"2019","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"774","DOI":"10.1002\/1873-3468.12591","article-title":"Altered lysosome distribution is an early neuropathological event in neurological forms of Gaucher disease","volume":"591","author":"Zigdon","year":"2017","journal-title":"FEBS Lett."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2075","DOI":"10.1007\/s00018-011-0913-1","article-title":"Neuronal ceroid lipofuscinosis protein CLN3 interacts with motor proteins and modifies location of late endosomal compartments","volume":"69","author":"Kyttala","year":"2012","journal-title":"Cell. Mol. Life Sci. CMLS"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1038\/ncb3324","article-title":"A molecular mechanism to regulate lysosome motility for lysosome positioning and tubulation","volume":"18","author":"Li","year":"2016","journal-title":"Nat. Cell Biol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.cell.2007.12.018","article-title":"Autophagy in the pathogenesis of disease","volume":"132","author":"Levine","year":"2008","journal-title":"Cell"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"590","DOI":"10.4161\/auto.6259","article-title":"Neurodegenerative lysosomal disorders: A continuum from development to late age","volume":"4","author":"Nixon","year":"2008","journal-title":"Autophagy"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"E3699","DOI":"10.1073\/pnas.1510329112","article-title":"Massive accumulation of luminal protease-deficient axonal lysosomes at Alzheimer\u2019s disease amyloid plaques","volume":"112","author":"Gowrishankar","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1259","DOI":"10.1242\/jcs.161216","article-title":"Autophagosome dynamics in neurodegeneration at a glance","volume":"128","author":"Wong","year":"2015","journal-title":"J. Cell Sci."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1016\/j.neuron.2015.06.026","article-title":"Endolysosomal Deficits Augment Mitochondria Pathology in Spinal Motor Neurons of Asymptomatic fALS Mice","volume":"87","author":"Xie","year":"2015","journal-title":"Neuron"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1350","DOI":"10.1093\/hmg\/ddr573","article-title":"Roles of the Drosophila LRRK2 homolog in Rab7-dependent lysosomal positioning","volume":"21","author":"Dodson","year":"2012","journal-title":"Hum. Mol. Genet."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1941","DOI":"10.1111\/ejn.12957","article-title":"Altered lysosomal positioning affects lysosomal functions in a cellular model of Huntington\u2019s disease","volume":"42","author":"Erie","year":"2015","journal-title":"Eur. J. Neurosci."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"855","DOI":"10.1083\/jcb.108.3.855","article-title":"Changes in lysosome shape and distribution correlated with changes in cytoplasmic pH","volume":"108","author":"Heuser","year":"1989","journal-title":"J. Cell Biol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"14693","DOI":"10.18632\/oncotarget.7492","article-title":"Obatoclax impairs lysosomal function to block autophagy in cisplatin-sensitive and -resistant esophageal cancer cells","volume":"7","author":"Yu","year":"2016","journal-title":"Oncotarget"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1436","DOI":"10.1126\/science.aaf2693","article-title":"NAD(+) repletion improves mitochondrial and stem cell function and enhances life span in mice","volume":"352","author":"Zhang","year":"2016","journal-title":"Science"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1016\/j.jbior.2016.10.002","article-title":"Ceramidases, roles in sphingolipid metabolism and in health and disease","volume":"63","author":"Coant","year":"2017","journal-title":"Adv. Biol. Regul."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"14486","DOI":"10.1016\/S0021-9258(18)98712-0","article-title":"Inhibition of sphingolipid biosynthesis by fumonisins. Implications for diseases associated with Fusarium moniliforme","volume":"266","author":"Wang","year":"1991","journal-title":"J. Biol. Chem."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"393","DOI":"10.3109\/00365517109080235","article-title":"Ceramides in a patient with lipogranulomatosis (Farber\u2019s disease) with chronic course","volume":"27","author":"Samuelsson","year":"1971","journal-title":"Scand. J. Clin. Lab. Investig."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1210\/me.2011-1150","article-title":"Acid ceramidase (ASAH1) is a global regulator of steroidogenic capacity and adrenocortical gene expression","volume":"26","author":"Lucki","year":"2012","journal-title":"Mol. Endocrinol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1590","DOI":"10.1194\/jlr.RA119000251","article-title":"Chemotherapy selection pressure alters sphingolipid composition and mitochondrial bioenergetics in resistant HL-60 cells","volume":"60","author":"Kao","year":"2019","journal-title":"J. Lipid Res."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"7411","DOI":"10.1038\/s41598-017-07606-w","article-title":"Complete Acid Ceramidase ablation prevents cancer-initiating cell formation in melanoma cells","volume":"7","author":"Lai","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1225","DOI":"10.1194\/jlr.M092247","article-title":"Genetic and pharmacological inhibition of acid ceramidase prevents asymmetric cell division by neosis","volume":"60","author":"Lu","year":"2019","journal-title":"J. Lipid Res."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1183","DOI":"10.1515\/hsz-2018-0170","article-title":"Pathological manifestations of Farber disease in a new mouse model","volume":"399","author":"Beckmann","year":"2018","journal-title":"Biol. Chem."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1572","DOI":"10.1038\/s41374-019-0271-4","article-title":"Hepatic pathology and altered gene transcription in a murine model of acid ceramidase deficiency","volume":"99","author":"Yu","year":"2019","journal-title":"Lab. Investig. J. Tech. Methods Pathol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1002\/emmm.201202301","article-title":"Systemic ceramide accumulation leads to severe and varied pathological consequences","volume":"5","author":"Alayoubi","year":"2013","journal-title":"EMBO Mol. Med."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1016\/j.bbalip.2008.06.002","article-title":"Ceramidases: Regulators of cellular responses mediated by ceramide, sphingosine, and sphingosine-1-phosphate","volume":"1781","author":"Mao","year":"2008","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1002\/ana.24170","article-title":"Impairment of ceramide synthesis causes a novel progressive myoclonus epilepsy","volume":"76","author":"Vanni","year":"2014","journal-title":"Ann. Neurol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/j.neurobiolaging.2016.03.027","article-title":"Loss of ceramide synthase 2 activity, necessary for myelin biosynthesis, precedes tau pathology in the cortical pathogenesis of Alzheimer\u2019s disease","volume":"43","author":"Couttas","year":"2016","journal-title":"Neurobiol. Aging"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1002\/acn3.28","article-title":"Reduced ceramide synthase 2 activity causes progressive myoclonic epilepsy","volume":"1","author":"Mosbech","year":"2014","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1002\/mdc3.12610","article-title":"Progressive Myoclonic Epilepsy Type 8 Due to CERS1 Deficiency: A Novel Mutation with Prominent Ataxia","volume":"5","author":"Vale","year":"2018","journal-title":"Mov. Disord. Clin. Pract."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1111\/cge.12307","article-title":"Evidence for clinical, genetic and biochemical variability in spinal muscular atrophy with progressive myoclonic epilepsy","volume":"86","author":"Dyment","year":"2014","journal-title":"Clin. Genet."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"959","DOI":"10.1016\/j.nmd.2015.09.007","article-title":"Acid ceramidase deficiency associated with spinal muscular atrophy with progressive myoclonic epilepsy","volume":"25","author":"Gan","year":"2015","journal-title":"Neuromuscul. Disord. NMD"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1016\/j.nmd.2014.11.007","article-title":"Uniparental disomy as a cause of spinal muscular atrophy and progressive myoclonic epilepsy: Phenotypic homogeneity due to the homozygous c.125C>T mutation in ASAH1","volume":"25","author":"Giraldez","year":"2015","journal-title":"Neuromuscul. Disord. NMD"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"692","DOI":"10.1111\/epi.12977","article-title":"Spinal muscular atrophy associated with progressive myoclonic epilepsy: A rare condition caused by mutations in ASAH1","volume":"56","author":"Rubboli","year":"2015","journal-title":"Epilepsia"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"32978","DOI":"10.1074\/jbc.M301936200","article-title":"Purification and characterization of recombinant, human acid ceramidase. Catalytic reactions and interactions with acid sphingomyelinase","volume":"278","author":"He","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1038\/42408","article-title":"Functional rafts in cell membranes","volume":"387","author":"Simons","year":"1997","journal-title":"Nature"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"10670","DOI":"10.1021\/bi00499a014","article-title":"Interaction of cholesterol with various glycerophospholipids and sphingomyelin","volume":"29","author":"Sankaram","year":"1990","journal-title":"Biochemistry"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1038\/35036052","article-title":"Lipid rafts and signal transduction","volume":"1","author":"Simons","year":"2000","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"542","DOI":"10.1016\/j.conb.2004.08.003","article-title":"Spatial and temporal control of signaling through lipid rafts","volume":"14","author":"Golub","year":"2004","journal-title":"Curr. Opin. Neurobiol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1016\/S0166-2236(02)02215-4","article-title":"Lipid rafts in neuronal signaling and function","volume":"25","author":"Encinas","year":"2002","journal-title":"Trends Neurosci."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.bbamem.2005.02.014","article-title":"Molecular associations and surface-active properties of short- and long-N-acyl chain ceramides","volume":"1711","author":"Sot","year":"2005","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"11788","DOI":"10.1074\/jbc.M111568200","article-title":"Membrane restructuring via ceramide results in enhanced solute efflux","volume":"277","author":"Montes","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"2867","DOI":"10.1529\/biophysj.108.129858","article-title":"Membrane domain formation, interdigitation, and morphological alterations induced by the very long chain asymmetric C24:1 ceramide","volume":"95","author":"Pinto","year":"2008","journal-title":"Biophys. J."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"1117","DOI":"10.1007\/s00249-009-0562-6","article-title":"Ceramide acyl chain length markedly influences miscibility with palmitoyl sphingomyelin in bilayer membranes","volume":"39","author":"Westerlund","year":"2010","journal-title":"Eur. Biophys. J. EBJ"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"1283","DOI":"10.1016\/j.cell.2006.01.040","article-title":"A lentiviral RNAi library for human and mouse genes applied to an arrayed viral high-content screen","volume":"124","author":"Moffat","year":"2006","journal-title":"Cell"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1098","DOI":"10.1126\/science.1106148","article-title":"Phosphorylation and regulation of Akt\/PKB by the rictor-mTOR complex","volume":"307","author":"Sarbassov","year":"2005","journal-title":"Science"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"8957","DOI":"10.1128\/JVI.77.16.8957-8951.2003","article-title":"Conditional suppression of cellular genes: Lentivirus vector-mediated drug-inducible RNA interference","volume":"77","author":"Wiznerowicz","year":"2003","journal-title":"J. Virol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"e36","DOI":"10.1093\/nar\/30.9.e36","article-title":"Relative expression software tool (REST) for group-wise comparison and statistical analysis of relative expression results in real-time PCR","volume":"30","author":"Pfaffl","year":"2002","journal-title":"Nucleic Acids Res."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"642","DOI":"10.1002\/cbic.200600533","article-title":"Synthesis of a novel ceramide analogue and its use in a high-throughput fluorogenic assay for ceramidases","volume":"8","author":"Bedia","year":"2007","journal-title":"Chembiochem"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"3542","DOI":"10.1194\/jlr.D010033","article-title":"A simple fluorogenic method for determination of acid ceramidase activity and diagnosis of Farber disease","volume":"51","author":"Bedia","year":"2010","journal-title":"J. Lipid Res."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1007\/s10616-005-2551-7","article-title":"Evaluation of a continuous quantification method of apoptosis and necrosis in tissue cultures","volume":"46","author":"Gawlitta","year":"2004","journal-title":"Cytotechnology"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1083\/jcb.66.1.188","article-title":"Rapid flow cytofluorometric analysis of mammalian cell cycle by propidium iodide staining","volume":"66","author":"Krishan","year":"1975","journal-title":"J. Cell Biol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/0003-2697(85)90442-7","article-title":"Measurement of protein using bicinchoninic acid","volume":"150","author":"Smith","year":"1985","journal-title":"Anal. Biochem."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1007\/978-1-60761-322-0_22","article-title":"Comprehensive quantitative analysis of bioactive sphingolipids by high-performance liquid chromatography-tandem mass spectrometry","volume":"579","author":"Bielawski","year":"2009","journal-title":"Methods Mol. Biol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/5\/1607\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:02:00Z","timestamp":1760173320000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/5\/1607"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,2,26]]},"references-count":99,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2020,3]]}},"alternative-id":["ijms21051607"],"URL":"https:\/\/doi.org\/10.3390\/ijms21051607","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,2,26]]}}}