{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T18:50:59Z","timestamp":1792608659225,"version":"4.5.0"},"reference-count":57,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,6,7]],"date-time":"2024-06-07T00:00:00Z","timestamp":1717718400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurosci."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a rare incurable neurodegenerative disease caused by mutations in the <jats:italic>SACS<\/jats:italic> gene, which codes for sacsin, a large protein involved in protein homeostasis, mitochondrial function, cytoskeletal dynamics, autophagy, cell adhesion and vesicle trafficking. However, the pathogenic mechanisms underlying sacsin dysfunction are still largely uncharacterized, and so attempts to develop therapies are still in the early stages.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>To achieve further understanding of how processes are altered by loss of sacsin, we used untargeted proteomics to compare protein profiles in ARSACS fibroblasts versus controls.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Our analyses confirmed the involvement of known biological pathways and also implicated calcium and lipid homeostasis in ARSACS skin fibroblasts, a finding further verified in SH-SY5Y <jats:italic>SACS<\/jats:italic><jats:sup>\u2013\/\u2013<\/jats:sup> cells. Validation through mass spectrometry-based analysis and comparative quantification of lipids by LC-MS in fibroblasts revealed increased levels of ceramides coupled with a reduction of diacylglycerols.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>In addition to confirming aberrant Ca<jats:sup>2+<\/jats:sup> homeostasis in ARSACS, this study described abnormal lipid levels associated with loss of sacsin.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fnins.2024.1375299","type":"journal-article","created":{"date-parts":[[2024,6,11]],"date-time":"2024-06-11T18:18:20Z","timestamp":1718129900000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["Proteomics and lipidomic analysis reveal dysregulated pathways associated with loss of sacsin"],"prefix":"10.3389","volume":"18","author":[{"given":"Daniele","family":"Galatolo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Rocchiccioli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicoletta","family":"Di Giorgi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Flavio","family":"Dal Canto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanni","family":"Signore","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federica","family":"Morani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisa","family":"Ceccherini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefano","family":"Doccini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Filippo Maria","family":"Santorelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,6,7]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"4253","DOI":"10.1113\/JP275902","article-title":"Altered synaptic and firing properties of cerebellar Purkinje cells in a mouse model of ARSACS.","volume":"596","author":"Ady","year":"2018","journal-title":"J. Physiol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1146\/annurev.genom.9.081307.164204","article-title":"The role of aminoacyl-tRNA synthetases in genetic diseases.","volume":"9","author":"Antonellis","year":"2008","journal-title":"Annu. Rev. Genomics Hum. Genet."},{"key":"B3","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3390\/cells11040706","article-title":"Interaction of mitochondrial calcium and ROS in neurodegeneration.","volume":"11","author":"Baev","year":"2022","journal-title":"Cells"},{"key":"B4","doi-asserted-by":"publisher","first-page":"441","DOI":"10.1007\/s10048-010-0249-2","article-title":"A new locus (SPG46) maps to 9p21.2-q21.12 in a Tunisian family with a complicated autosomal recessive hereditary spastic paraplegia with mental impairment and thin corpus callosum.","volume":"11","author":"Boukhris","year":"2010","journal-title":"Neurogenetics"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.3390\/ijms19103010","article-title":"Exogenous C8-ceramide induces apoptosis by overproduction of ROS and the switch of superoxide dismutases SOD1.","volume":"19","author":"Chang","year":"2018","journal-title":"Int. J. Mol. Sci."},{"key":"B6","doi-asserted-by":"publisher","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":"B7","doi-asserted-by":"publisher","first-page":"5436","DOI":"10.1007\/s12035-018-1448-3","article-title":"The role of ceramide and sphingosine-1-phosphate in Alzheimer\u2019s disease and other neurodegenerative disorders.","volume":"56","author":"Czubowicz","year":"2019","journal-title":"Mol. Neurobiol."},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.163576","article-title":"Restoring calcium homeostasis in Purkinje cells arrests neurodegeneration and neuroinflammation in the ARSACS mouse model.","volume":"8","author":"Del Bondio","year":"2023","journal-title":"JCI Insight"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.3390\/biom12060738","article-title":"Salivary proteomics markers for preclinical Sj\u00f6gren\u2019s syndrome: A pilot study.","volume":"12","author":"Di Giorgi","year":"2022","journal-title":"Biomolecules"},{"key":"B10","doi-asserted-by":"publisher","first-page":"248","DOI":"10.1212\/01.wnl.0000319610.29522.8a","article-title":"A novel locus for an autosomal recessive hereditary spastic paraplegia (SPG35) maps to 16q21-q23.","volume":"71","author":"Dick","year":"2008","journal-title":"Neurology"},{"key":"B11","doi-asserted-by":"publisher","first-page":"4281","DOI":"10.1021\/ac051632c","article-title":"Probabilistic quotient normalization as robust method to account for dilution of complex biological mixtures. Application in1H NMR metabonomics.","volume":"78","author":"Dieterle","year":"2006","journal-title":"Anal. Chem."},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.3390\/cells11111840","article-title":"Lysosomal proteomics links disturbances in lipid homeostasis and sphingolipid metabolism to CLN5 disease.","volume":"11","author":"Doccini","year":"2022","journal-title":"Cells"},{"key":"B13","doi-asserted-by":"publisher","first-page":"1535","DOI":"10.1089\/ars.2007.1692","article-title":"Ceramide: A novel player in reactive oxygen species-induced signaling?","volume":"9","author":"Dumitru","year":"2007","journal-title":"Antioxid. Redox Signal."},{"key":"B14","doi-asserted-by":"publisher","first-page":"3130","DOI":"10.1093\/hmg\/ddx197","article-title":"Altered organization of the intermediate filament cytoskeleton and relocalization of proteostasis modulators in cells lacking the ataxia protein sacsin.","volume":"26","author":"Duncan","year":"2017","journal-title":"Hum. Mol. Genet."},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2021.732319","article-title":"Phospholipases and reactive oxygen species derived lipid biomarkers in healthy and diseased humans and animals \u2013 A focus on lysophosphatidylcholine.","volume":"12","author":"Engel","year":"2021","journal-title":"Front. Physiol."},{"key":"B16","doi-asserted-by":"publisher","first-page":"120","DOI":"10.1038\/72769","article-title":"ARSACS, a spastic ataxia common in northeastern Quebec, is caused by mutations in a new gene encoding an 11.5-kb ORF.","volume":"24","author":"Engert","year":"2000","journal-title":"Nat. Genet."},{"key":"B17","doi-asserted-by":"publisher","first-page":"497","DOI":"10.1016\/s0021-9258(18)64849-5","article-title":"A simple method for the isolation and purification of total lipides from animal tissues.","volume":"226","author":"Folch","year":"1957","journal-title":"J. Biol. Chem."},{"key":"B18","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/978-1-4419-6741-1_1","article-title":"An overview of sphingolipid metabolism.","volume":"688","author":"Gault","year":"2010","journal-title":"Adv. Exp. Med. Biol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"1661","DOI":"10.1073\/pnas.1113166109","article-title":"Mitochondrial dysfunction and Purkinje cell loss in autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS).","volume":"109","author":"Girard","year":"2012","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"B20","doi-asserted-by":"publisher","first-page":"175","DOI":"10.1038\/nrm.2017.107","article-title":"Sphingolipids and their metabolism in physiology and disease.","volume":"19","author":"Hannun","year":"2018","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1038\/nprot.2008.211","article-title":"Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources.","volume":"4","author":"Huang","year":"2009","journal-title":"Nat. Protoc."},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-020-2418-z","article-title":"Caveolin-1 regulates the ASMase\/ceramide-mediated radiation response of endothelial cells in the context of tumor\u2013stroma interactions.","volume":"11","author":"Ketteler","year":"2020","journal-title":"Cell Death Dis."},{"key":"B23","doi-asserted-by":"publisher","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":"B24","doi-asserted-by":"publisher","first-page":"2424","DOI":"10.1093\/hmg\/ddac047","article-title":"Lysosomal ceramides regulate cathepsin B-mediated processing of saposin C and glucocerebrosidase activity.","volume":"31","author":"Kim","year":"2022","journal-title":"Hum. Mol. Genet."},{"key":"B25","doi-asserted-by":"publisher","first-page":"961","DOI":"10.1007\/s00401-021-02367-3","article-title":"Altered ceramide metabolism is a feature in the extracellular vesicle-mediated spread of alpha-synuclein in Lewy body disorders.","volume":"142","author":"Kurzawa-Akanbi","year":"2021","journal-title":"Acta Neuropathol."},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.00364-23","article-title":"The small GTPase Rab14 regulates the trafficking of ceramide from endoplasmic reticulum to golgi apparatus and facilitates classical swine fever virus assembly.","volume":"97","author":"Liu","year":"2023","journal-title":"J. Virol."},{"key":"B27","doi-asserted-by":"publisher","first-page":"e2315","DOI":"10.1212\/WNL.0000000000012962","article-title":"Assessment of sacsin turnover in patients with ARSACS.","volume":"97","author":"Longo","year":"2021","journal-title":"Neurology"},{"key":"B28","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1155\/2023\/1496597","article-title":"In vitro characterization of motor neurons and Purkinje cells differentiated from induced pluripotent stem cells generated from patients with autosomal recessive spastic ataxia of charlevoix-Saguenay.","volume":"2023","author":"Louit","year":"2023","journal-title":"Stem Cells Int."},{"key":"B29","doi-asserted-by":"publisher","first-page":"3448","DOI":"10.1093\/bioinformatics\/bti551","article-title":"BiNGO: A cytoscape plugin to assess overrepresentation of gene ontology categories in biological networks.","volume":"21","author":"Maere","year":"2005","journal-title":"Bioinformatics"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.3390\/ijms242316901","article-title":"Opaganib (ABC294640) induces immunogenic tumor cell death and enhances checkpoint antibody therapy.","volume":"24","author":"Maines","year":"2023","journal-title":"Int. J. Mol. Sci."},{"key":"B31","doi-asserted-by":"publisher","first-page":"12451","DOI":"10.1021\/acsomega.0c01282","article-title":"Development of nanostructured lipid carriers for the delivery of idebenone in autosomal recessive spastic ataxia of charlevoix-Saguenay.","volume":"5","author":"Martinelli","year":"2020","journal-title":"ACS Omega"},{"key":"B32","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41598-021-92339-0","article-title":"Lipid biomarkers in statin users with coronary artery disease annotated by coronary computed tomography angiography.","volume":"11","author":"Michelucci","year":"2021","journal-title":"Sci. Rep."},{"key":"B33","doi-asserted-by":"publisher","first-page":"2890","DOI":"10.1021\/acs.jproteome.0c00082","article-title":"Lipidr: A software tool for data mining and analysis of lipidomics datasets.","volume":"19","author":"Mohamed","year":"2020","journal-title":"J. Proteome Res."},{"key":"B34","doi-asserted-by":"publisher","first-page":"4117","DOI":"10.1093\/brain\/awad136","article-title":"SARM1 deletion delays cerebellar but not spinal cord degeneration in an enhanced mouse model of SPG7 deficiency.","volume":"146","author":"Montoro-G\u00e1mez","year":"2023","journal-title":"Brain"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2020.603774","article-title":"Functional network profiles in ARSACS disclosed by aptamer-based proteomic technology.","volume":"11","author":"Morani","year":"2021","journal-title":"Front. Neurol."},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.3390\/biom12081024","article-title":"Integrative organelle-based functional proteomics: In silico prediction of impaired functional annotations in SACS KO cell model.","volume":"12","author":"Morani","year":"2022","journal-title":"Biomolecules"},{"key":"B37","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41598-019-48047-x","article-title":"Functional transcriptome analysis in ARSACS KO cell model reveals a role of sacsin in autophagy.","volume":"9","author":"Morani","year":"2019","journal-title":"Sci. Rep."},{"key":"B38","doi-asserted-by":"publisher","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":"B39","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22168401","article-title":"Efficient neuroprotective rescue of sacsin-related disease phenotypes in zebrafish.","volume":"22","author":"Naef","year":"2021","journal-title":"Int. J. Mol. Sci."},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.3390\/ijms222111722","article-title":"Hsp90 inhibition: A promising therapeutic approach for ARSACS.","volume":"22","author":"Nethisinghe","year":"2021","journal-title":"Int. J. Mol. Sci."},{"key":"B41","doi-asserted-by":"publisher","first-page":"1334","DOI":"10.1016\/j.bbadis.2013.04.009","article-title":"Calcium and mitochondrial metabolism in ceramide-induced cardiomyocyte death.","volume":"1832","author":"Parra","year":"2013","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2020.00707","article-title":"Aberrant cerebellar circuitry in the spinocerebellar ataxias.","volume":"14","author":"Robinson","year":"2020","journal-title":"Front. Neurosci."},{"key":"B43","doi-asserted-by":"publisher","first-page":"525","DOI":"10.1002\/humu.22269","article-title":"Comparative analysis and functional mapping of SACS mutations reveal novel insights into sacsin repeated architecture.","volume":"34","author":"Romano","year":"2013","journal-title":"Hum. Mutat."},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2022.111580","article-title":"Multi-omic profiling reveals the ataxia protein sacsin is required for integrin trafficking and synaptic organization.","volume":"41","author":"Romano","year":"2022","journal-title":"Cell Rep."},{"key":"B45","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1016\/j.mcn.2015.03.013","article-title":"Glucocerebrosidase and Parkinson disease: Recent advances.","volume":"66","author":"Schapira","year":"2015","journal-title":"Mol. Cell. Neurosci."},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a035212","article-title":"Calcium-handling defects and neurodegenerative disease.","volume":"12","author":"Schrank","year":"2020","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"B47","doi-asserted-by":"publisher","first-page":"1638","DOI":"10.1074\/mcp.T600050-MCP200","article-title":"The paragon algorithm, a next generation search engine that uses sequence temperature values and feature probabilities to identify peptides from tandem mass spectra.","volume":"6","author":"Shilov","year":"2007","journal-title":"Mol. Cell. Proteomics"},{"key":"B48","doi-asserted-by":"publisher","first-page":"114","DOI":"10.1136\/jnnp-2012-303634","article-title":"The ARSACS phenotype can include supranuclear gaze palsy and skin lipofuscin deposits.","volume":"84","author":"Stevens","year":"2013","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"B49","doi-asserted-by":"publisher","first-page":"15545","DOI":"10.1073\/pnas.0506580102","article-title":"Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles.","volume":"102","author":"Subramanian","year":"2005","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2023.106157","article-title":"A mitochondrial-targeted antioxidant (MitoQ) improves motor coordination and reduces Purkinje cell death in a mouse model of ARSACS.","volume":"183","author":"Toscano M\u00e1rquez","year":"2023","journal-title":"Neurobiol. Dis."},{"key":"B51","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1002\/cem.695","article-title":"Orthogonal projections to latent structures (O-PLS).","volume":"16","author":"Trygg","year":"2002","journal-title":"J. Chemom."},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1016\/j.jlr.2022.100255","article-title":"Skin fibroblast metabolomic profiling reveals that lipid dysfunction predicts the severity of Friedreich\u2019s ataxia.","volume":"63","author":"Wang","year":"2022","journal-title":"J. Lipid Res."},{"key":"B53","doi-asserted-by":"publisher","first-page":"80","DOI":"10.1136\/jmg.2004.020172","article-title":"A new locus for autosomal recessive complicated hereditary spastic paraplegia (SPG26) maps to chromosome 12p11.1-12q14.","volume":"42","author":"Wilkinson","year":"2005","journal-title":"J. Med. Genet."},{"key":"B54","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1007\/s00401-012-1026-0","article-title":"The many faces of plectin and plectinopathies: Pathology and mechanisms.","volume":"125","author":"Winter","year":"2013","journal-title":"Acta Neuropathol."},{"key":"B55","doi-asserted-by":"publisher","first-page":"97","DOI":"10.2174\/2213235X04666160613122429","article-title":"PCA as a practical indicator of OPLS-DA model reliability.","volume":"4","author":"Worley","year":"2016","journal-title":"Curr. Metab."},{"key":"B56","doi-asserted-by":"publisher","first-page":"131","DOI":"10.1007\/s12031-019-01410-z","article-title":"A novel homozygous SACS mutation identified by whole exome sequencing-genotype phenotype correlations of all published cases.","volume":"70","author":"Xiromerisiou","year":"2020","journal-title":"J. Mol. Neurosci."},{"key":"B57","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1194\/jlr.R031278","article-title":"Sphingolipids: Regulators of crosstalk between apoptosis and autophagy.","volume":"54","author":"Young","year":"2013","journal-title":"J. Lipid Res."}],"container-title":["Frontiers in Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnins.2024.1375299\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,6,11]],"date-time":"2024-06-11T18:18:22Z","timestamp":1718129902000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnins.2024.1375299\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,6,7]]},"references-count":57,"alternative-id":["10.3389\/fnins.2024.1375299"],"URL":"https:\/\/doi.org\/10.3389\/fnins.2024.1375299","relation":{},"ISSN":["1662-453X"],"issn-type":[{"value":"1662-453X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,6,7]]},"article-number":"1375299"}}