{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,6]],"date-time":"2026-05-06T08:53:28Z","timestamp":1778057608803,"version":"3.51.4"},"reference-count":49,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2020,9,14]],"date-time":"2020-09-14T00:00:00Z","timestamp":1600041600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"European Commission Research Executive Agency (REA)","award":["BIORISE 669026"],"award-info":[{"award-number":["BIORISE 669026"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Spastic ataxia (SA) is a group of rare neurodegenerative diseases, characterized by mixed features of generalized ataxia and spasticity. The pathogenetic mechanisms that drive the development of the majority of these diseases remain unclear, although a number of studies have highlighted the involvement of mitochondrial and lipid metabolism, as well as calcium signaling. Our group has previously published the GBA2 c.1780G &gt; C (p.Asp594His) missense variant as the cause of spastic ataxia in a Cypriot consanguineous family, and more recently the biochemical characterization of this variant in patients\u2019 lymphoblastoid cell lines. GBA2 is a crucial enzyme of sphingolipid metabolism. However, it is unknown if GBA2 has additional functions and therefore additional pathways may be involved in the disease development. The current study introduces bioinformatics approaches to better understand the pathogenetic mechanisms of the disease. We analyzed publicly available human gene expression datasets of diseases presented with \u2018ataxia\u2019 or \u2018spasticity\u2019 in their clinical phenotype and we performed pathway analysis in order to: (a) search for candidate perturbed pathways of SA; and (b) evaluate the role of sphingolipid signaling pathway and sphingolipid metabolism in the disease development, through the identification of differentially expressed genes in patients compared to controls. Our results demonstrate consistent differential expression of genes that participate in the sphingolipid pathways and highlight alterations in the pathway level that might be associated with the disease phenotype. Through enrichment analysis, we discuss additional pathways that are connected to sphingolipid pathways, such as PI3K-Akt signaling, MAPK signaling, calcium signaling, and lipid and carbohydrate metabolism as the most enriched for ataxia and spasticity phenotypes.<\/jats:p>","DOI":"10.3390\/ijms21186722","type":"journal-article","created":{"date-parts":[[2020,9,14]],"date-time":"2020-09-14T09:04:53Z","timestamp":1600074293000},"page":"6722","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Analyzing Gene Expression Profiles from Ataxia and Spasticity Phenotypes to Reveal Spastic Ataxia Related Pathways"],"prefix":"10.3390","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2982-679X","authenticated-orcid":false,"given":"Andrea C.","family":"Kakouri","sequence":"first","affiliation":[{"name":"Department of Bioinformatics, The Cyprus Institute of Neurology and Genetics, Nicosia 2370, Cyprus"},{"name":"Department of Neurogenetics, The Cyprus Institute of Neurology and Genetics, Nicosia 2370, Cyprus"},{"name":"The Cyprus School of Molecular Medicine, The Cyprus Institute of Neurology and Genetics, Nicosia 2370, Cyprus"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christina","family":"Votsi","sequence":"additional","affiliation":[{"name":"Department of Neurogenetics, The Cyprus Institute of Neurology and Genetics, Nicosia 2370, Cyprus"},{"name":"The Cyprus School of Molecular Medicine, The Cyprus Institute of Neurology and Genetics, Nicosia 2370, Cyprus"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0836-5579","authenticated-orcid":false,"given":"Marios","family":"Tomazou","sequence":"additional","affiliation":[{"name":"Department of Bioinformatics, The Cyprus Institute of Neurology and Genetics, Nicosia 2370, Cyprus"},{"name":"The Cyprus School of Molecular Medicine, The Cyprus Institute of Neurology and Genetics, Nicosia 2370, Cyprus"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"George","family":"Minadakis","sequence":"additional","affiliation":[{"name":"Department of Bioinformatics, The Cyprus Institute of Neurology and Genetics, Nicosia 2370, Cyprus"},{"name":"The Cyprus School of Molecular Medicine, The Cyprus Institute of Neurology and Genetics, Nicosia 2370, Cyprus"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Evangelos","family":"Karatzas","sequence":"additional","affiliation":[{"name":"Institute for Fundamental Biomedical Research, BSRC \u201cAlexander Fleming\u201d, 16672 Vari, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0622-7594","authenticated-orcid":false,"given":"Kyproula","family":"Christodoulou","sequence":"additional","affiliation":[{"name":"Department of Neurogenetics, The Cyprus Institute of Neurology and Genetics, Nicosia 2370, Cyprus"},{"name":"The Cyprus School of Molecular Medicine, The Cyprus Institute of Neurology and Genetics, Nicosia 2370, Cyprus"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2470-3363","authenticated-orcid":false,"given":"George M.","family":"Spyrou","sequence":"additional","affiliation":[{"name":"Department of Bioinformatics, The Cyprus Institute of Neurology and Genetics, Nicosia 2370, Cyprus"},{"name":"The Cyprus School of Molecular Medicine, The Cyprus Institute of Neurology and Genetics, Nicosia 2370, Cyprus"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,9,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1507","DOI":"10.1212\/WNL.0b013e31826d5fb0","article-title":"Warrenburg Reviewing the genetic causes of spastic-ataxias","volume":"79","author":"Willemsen","year":"2012","journal-title":"Neurology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1016\/B978-0-444-64189-2.00012-3","article-title":"Spastic ataxias","volume":"155","author":"Bereznyakova","year":"2018","journal-title":"Handbook of Clinical Neurology"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1324","DOI":"10.1002\/humu.22132","article-title":"The inherited ataxias: Genetic heterogeneity, mutation databases, and future directions in research and clinical diagnostics","volume":"33","author":"Hersheson","year":"2012","journal-title":"Hum. Mutat."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Noreau, A., Dupr\u00e9, N., Bouchard, J.P., Dion, P.A., and Rouleau, G.A. (2013). Autosomal recessive cerebellar Ataxias. Handbook of the Cerebellum and Cerebellar Disorders, Springer.","DOI":"10.1007\/978-94-007-1333-8_100"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1111\/ahg.12045","article-title":"A Novel GBA2 Gene Missense Mutation in Spastic Ataxia","volume":"78","author":"Votsi","year":"2014","journal-title":"Ann. Hum. Genet."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1561","DOI":"10.1093\/brain\/awx095","article-title":"Hypomorphic mutations in POLR3A are a frequent cause of sporadic and recessive spastic ataxia","volume":"140","author":"Minnerop","year":"2017","journal-title":"Brain"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"969","DOI":"10.1016\/j.ajhg.2017.05.009","article-title":"Mutations in NKX6-2 Cause Progressive Spastic Ataxia and Hypomyelination","volume":"100","author":"Chelban","year":"2017","journal-title":"Am. J. Hum. Genet."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1305","DOI":"10.1074\/jbc.M610544200","article-title":"Identification of the non-lysosomal glucosylceramidase as \u03b2-glucosidase 2","volume":"282","author":"Boot","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.bbrc.2015.07.112","article-title":"Lack of enzyme activity in GBA2 mutants associated with hereditary spastic paraplegia\/cerebellar ataxia (SPG46)","volume":"465","author":"Sultana","year":"2015","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Malekkou, A., Samarani, M., Drousiotou, A., Votsi, C., Aureli, M., Loberto, N., and Christodoulou, K. (2018). Biochemical Characterization of the GBA2 c. 1780G > C Missense Mutation in Lymphoblastoid Cells from Patients with Spastic Ataxia. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19103099"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1291","DOI":"10.1073\/pnas.0711257105","article-title":"The insulin-like growth factor pathway is altered in spinocerebellar ataxia type 1 and type 7","volume":"105","author":"Gatchel","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1194","DOI":"10.1016\/j.neuron.2016.02.011","article-title":"Cerebellar Transcriptome Profiles of ATXN1 Transgenic Mice Reveal SCA1 Disease Progression and Protection Pathways","volume":"89","author":"Ingram","year":"2016","journal-title":"Neuron"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2535","DOI":"10.1093\/hmg\/ddh268","article-title":"Gene profiling links SCA1 pathophysiology to glutamate signaling in Purkinje cells of transgenic mice","volume":"13","author":"Serra","year":"2004","journal-title":"Hum. Mol. Genet."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"e39981","DOI":"10.7554\/eLife.39981","article-title":"Molecular pathway analysis towards understanding tissue vulnerability in spinocerebellar ataxia type 1","volume":"7","author":"Driessen","year":"2018","journal-title":"Elife"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1353","DOI":"10.1242\/dmm.030536","article-title":"Comprehensive analysis of gene expression patterns in Friedreich\u2019s ataxia fibroblasts by RNA sequencing reveals altered levels of protein synthesis factors and solute carriers","volume":"10","author":"Napierala","year":"2017","journal-title":"DMM Dis. Model. Mech."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13024-018-0261-9","article-title":"Transcriptional profiling and biomarker identification reveal tissue specific effects of expanded ataxin-3 in a spinocerebellar ataxia type 3 mouse model","volume":"13","author":"Toonen","year":"2018","journal-title":"Mol. Neurodegener."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Gerstner, N., Kehl, T., Lenhof, K., M\u00fcller, A., Mayer, C., Eckhart, L., Grammes, N.L., Diener, C., Hart, M., and Hahn, O. (2020). GeneTrail 3: Advanced high-throughput enrichment analysis. Nucleic Acids Res.","DOI":"10.1093\/nar\/gkaa306"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Karatzas, E., Zachariou, M., Bourdakou, M.M., Minadakis, G., Oulas, A., Kolios, G., Delis, A., and Spyrou, G.M. (2020). PathWalks: Identifying pathway communities using a disease-related map of integrated information. Bioinformatics.","DOI":"10.1101\/2020.01.27.921270"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"D607","DOI":"10.1093\/nar\/gky1131","article-title":"STRING v11: Protein\u2013protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets","volume":"47","author":"Szklarczyk","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2498","DOI":"10.1101\/gr.1239303","article-title":"Cytoscape: A software Environment for integrated models of biomolecular interaction networks","volume":"13","author":"Shannon","year":"2003","journal-title":"Genome Res."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Riboldi, G.M., and Di Fonzo, A.B. (2019). GBA, Gaucher Disease, and Parkinson\u2019s Disease: From Genetic to Clinic to New Therapeutic Approaches. Cells, 8.","DOI":"10.3390\/cells8040364"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1007\/s12035-013-8606-4","article-title":"Ceramide in the Molecular Mechanisms of Neuronal Cell Death. The Role of Sphingosine-1-Phosphate","volume":"50","author":"Czubowicz","year":"2014","journal-title":"Mol. Neurobiol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1016\/j.tem.2018.11.003","article-title":"Sphingolipids in the Pathogenesis of Parkinson\u2019s Disease and Parkinsonism","volume":"30","author":"Lin","year":"2019","journal-title":"Trends Endocrinol. Metab."},{"key":"ref_24","unstructured":"(2020, February 01). KEGG: Kyoto Encyclopedia of Genes and Genomes. Available online: http:\/\/www.genome.jp\/kegg\/."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1038\/nrm3722","article-title":"Control of apoptosis by the BCL-2 protein family: Implications for physiology and therapy","volume":"15","author":"Czabotar","year":"2014","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2027","DOI":"10.1016\/j.bbamem.2006.10.018","article-title":"A house divided: Ceramide, sphingosine, and sphingosine-1-phosphate in programmed cell death","volume":"1758","author":"Taha","year":"2006","journal-title":"Biochim. Biophys. Acta Biomembr."},{"key":"ref_27","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_28","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1100\/tsw.2010.64","article-title":"Multiple functions of Phosphoinositide-3 Kinase Enhancer (PIKE)","volume":"10","author":"Chan","year":"2010","journal-title":"Sci. World J."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2721","DOI":"10.1523\/JNEUROSCI.4477-10.2011","article-title":"Phosphoinositide-3-kinase activation controls synaptogenesis and spinogenesis in hippocampal neurons","volume":"31","author":"Cuesto","year":"2011","journal-title":"J. Neurosci."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Bruel-Jungerman, E., Veyrac, A., Dufour, F., Horwood, J., Laroche, S., and Davis, S. (2009). Inhibition of PI3K-Akt signaling blocks exercise-mediated enhancement of adult neurogenesis and synaptic plasticity in the dentate gyrus. PLoS ONE, 4.","DOI":"10.1371\/journal.pone.0007901"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"S\u00e1nchez-Alegr\u00eda, K., Flores-Le\u00f3n, M., Avila-Mu\u00f1oz, E., Rodr\u00edguez-Corona, N., and Arias, C. (2018). PI3K signaling in neurons: A central node for the control of multiple functions. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19123725"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e1084","DOI":"10.1038\/cddis.2014.69","article-title":"Akt and mTOR mediate programmed necrosis in neurons","volume":"5","author":"Liu","year":"2014","journal-title":"Cell Death Dis."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/j.freeradbiomed.2014.06.023","article-title":"Insulin and IGF-1 improve mitochondrial function in a PI-3K\/Akt-dependent manner and reduce mitochondrial generation of reactive oxygen species in Huntington\u2019s disease knock-in striatal cells","volume":"74","author":"Ribeiro","year":"2014","journal-title":"Free Radic. Biol. Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/j.molmed.2009.01.001","article-title":"Calcium signaling and neurodegenerative diseases","volume":"15","author":"Bezprozvanny","year":"2009","journal-title":"Trends Mol. Med."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Sultana, S., Stewart, J., and van der Spoel, A.C. (2020). Truncated mutants of beta-glucosidase 2 (GBA2) are localized in the mitochondrial matrix and cause mitochondrial fragmentation. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0233856"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2755","DOI":"10.1007\/s00415-015-7911-4","article-title":"Powerhouse failure and oxidative damage in autosomal recessive spastic ataxia of Charlevoix-Saguenay","volume":"262","author":"Criscuolo","year":"2015","journal-title":"J. Neurol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1075","DOI":"10.1002\/ana.25220","article-title":"Mutations in VPS13D lead to a new recessive ataxia with spasticity and mitochondrial defects","volume":"83","author":"Seong","year":"2018","journal-title":"Ann. Neurol."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Crespo-Barreto, J., Fryer, J.D., Shaw, C.A., Orr, H.T., and Zoghbi, H.Y. (2010). Partial Loss of Ataxin-1 Function Contributes to Transcriptional Dysregulation in Spinocerebellar Ataxia Type 1 Pathogenesis. PLoS Genet., 6.","DOI":"10.1371\/journal.pgen.1001021"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1046\/j.1471-4159.2002.00827.x","article-title":"Oxygen and glucose deprivation induces mitochondrial dysfunction and oxidative stress in neurones but not in astrocytes in primary culture","volume":"81","author":"Almeida","year":"2002","journal-title":"J. Neurochem."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1240","DOI":"10.1016\/j.bbadis.2013.10.015","article-title":"Oxidative stress and mitochondrial dysfunction in Alzheimer\u2019s disease","volume":"1842","author":"Wang","year":"2014","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1738","DOI":"10.1096\/fj.01-1027com","article-title":"High glucose-induced oxidative stress and mitochondrial dysfunction in neurons","volume":"16","author":"Russell","year":"2002","journal-title":"FASEB J."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"3501","DOI":"10.1007\/s12035-018-1286-3","article-title":"The Cross-Talk between Sphingolipids and Insulin-Like Growth Factor Signaling: Significance for Aging and Neurodegeneration","volume":"56","author":"Lukiw","year":"2019","journal-title":"Mol. Neurobiol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1093\/nar\/30.1.207","article-title":"Gene Expression Omnibus: NCBI gene expression and hybridization array data repository","volume":"30","author":"Edgar","year":"2002","journal-title":"Nucleic Acids Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"e47","DOI":"10.1093\/nar\/gkv007","article-title":"Limma powers differential expression analyses for RNA-sequencing and microarray studies","volume":"43","author":"Ritchie","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Smyth, G.K. (2004). Linear models and empirical bayes methods for assessing differential expression in microarray experiments. Stat. Appl. Genet. Mol. Biol.","DOI":"10.2202\/1544-6115.1027"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"W90","DOI":"10.1093\/nar\/gkw377","article-title":"Enrichr: A comprehensive gene set enrichment analysis web server 2016 update","volume":"44","author":"Kuleshov","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"ref_47","unstructured":"Csardi, G. (2008). The Igraph Package Title Routines for Simple Graphs, Network Analysis, Department of Medical Genetics, University of Lausanne."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"815","DOI":"10.1109\/TCBB.2014.2361348","article-title":"ClusterViz: A Cytoscape APP for Cluster Analysis of Biological Network","volume":"12","author":"Wang","year":"2015","journal-title":"IEEE\/ACM Trans. Comput. Biol. Bioinforma."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Li, M., Wang, J., and Chen, J. (2008). A fast agglomerate algorithm for mining functional modules in protein interaction networks. BioMedical Engineering and Informatics: New Development and the Future, Proceedings of the 1st International Conference on BioMedical Engineering and Informatics, BMEI, Sanya, China, 27\u201330 May 2008, IEEE.","DOI":"10.1109\/BMEI.2008.121"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/18\/6722\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:09:45Z","timestamp":1760177385000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/18\/6722"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,9,14]]},"references-count":49,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2020,9]]}},"alternative-id":["ijms21186722"],"URL":"https:\/\/doi.org\/10.3390\/ijms21186722","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,9,14]]}}}