{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,5,14]],"date-time":"2025-05-14T04:18:45Z","timestamp":1747196325633,"version":"3.40.5"},"reference-count":53,"publisher":"Public Library of Science (PLoS)","issue":"2","license":[{"start":{"date-parts":[[2023,2,3]],"date-time":"2023-02-03T00:00:00Z","timestamp":1675382400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>It is well established that patients with Gaucher disease, as well as carriers of the disease have an increased risk for developing Parkinson\u2019s disease. A plethora of evidence suggests that disturbed \u03b1-Synuclein homeostasis is the link between Gaucher disease and Parkinson\u2019s disease. The pathogenic mechanism linking these entities is still a topic of debate and both gain- and loss-of-function theories have been put forward, which however are not mutually exclusive. In the present study we expanded our previous studies to include not only Gaucher disease patients but also Gaucher disease carriers and Gaucher disease patients following Enzyme Replacement Therapy. In these groups we investigated \u03b1-Synuclein in red blood cell membranes in association with lipid abnormalities described in Gaucher disease. These included glucosylceramide and its species, glucosylsphingosine, glucosylcholesterol and plasmalogens. Increased oligomerization of \u03b1-Synuclein in red blood cell membranes was observed not only in Gaucher disease patients but also in carriers of the disease. There were no qualitative differences in the lipids identified in the groups studied. However, significant quantitative differences compared to controls were observed in Gaucher disease patients but not in Gaucher disease carriers. Enzyme Replacement Therapy reversed the biochemical defects and normalized \u03b1-Synuclein homeostasis, providing for the first time evidence in human subjects that such homeostatic dysregulation is reversible. Further studies investigating \u03b1-Synuclein status during the differentiation of erythroid progenitors could provide new data on the pathogenic mechanism of \u03b1-Synuclein oligomerization in this system.<\/jats:p>","DOI":"10.1371\/journal.pone.0277602","type":"journal-article","created":{"date-parts":[[2023,2,3]],"date-time":"2023-02-03T18:33:03Z","timestamp":1675449183000},"page":"e0277602","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":2,"title":["a-Synuclein and lipids in erythrocytes of Gaucher disease carriers and patients before and after enzyme replacement therapy"],"prefix":"10.1371","volume":"18","author":[{"given":"Marina","family":"Moraitou","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1796-8010","authenticated-orcid":true,"given":"Georgios","family":"Sotiroudis","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nikolaos","family":"Papagiannakis","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria M. J.","family":"Ferraz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aristotelis","family":"Xenakis","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Johannes M. F. G.","family":"Aerts","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Leonidas","family":"Stefanis","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1858-891X","authenticated-orcid":true,"given":"Helen","family":"Michelakakis","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2023,2,3]]},"reference":[{"key":"pone.0277602.ref001","first-page":"3635","volume-title":"The Metabolic and Molecular Basis of Inherited Disease","author":"\u0395 Beutler","year":"2001"},{"key":"pone.0277602.ref002","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1016\/j.cbpa.2019.10.006","article-title":"Glycosphingolipids and lysosomal storage disorders as illustrated by gaucher disease","volume":"53","author":"JMFG Aerts","year":"2019","journal-title":"Curr. Opin. Chem. Biol"},{"key":"pone.0277602.ref003","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1016\/j.bcmd.2008.03.007","article-title":"Plasmalogen levels in Gaucher disease","volume":"41","author":"M Moraitou","year":"2008","journal-title":"Blood Cells Mol Dis"},{"key":"pone.0277602.ref004","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1016\/j.euroneuro.2005.04.007","article-title":"Prevalence and incidence of Parkinson\u2019s disease in Europe","volume":"15","author":"S von Campenhausen","year":"2005","journal-title":"Eur. Neuropsychopharmacol."},{"key":"pone.0277602.ref005","doi-asserted-by":"crossref","first-page":"6469","DOI":"10.1073\/pnas.95.11.6469","article-title":"alpha-Synuclein in filamentous inclusions of Lewy bodies from Parkinson\u2019s disease and dementia with Lewy bodies","volume":"95","author":"MG Spillantini","year":"1998","journal-title":"Proc. Natl. Acad. Sci. U S A"},{"key":"pone.0277602.ref006","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1186\/1750-1326-4-9","article-title":"alpha-Synuclein and neuronal cell death","volume":"4","author":"M. Cookson","year":"2009","journal-title":"Mol. Neurodegener"},{"key":"pone.0277602.ref007","doi-asserted-by":"crossref","first-page":"15561","DOI":"10.1039\/C4CP05883F","article-title":"Biophysics of \u03b1-synuclein induced membrane remodeling","volume":"17","author":"Z Shi","year":"2015","journal-title":"Phys Chem Chem Phys"},{"key":"pone.0277602.ref008","doi-asserted-by":"crossref","first-page":"7065","DOI":"10.1073\/pnas.1601899113","article-title":"Chemical properties of lipids strongly affect the kinetics of the membrane-induced aggregation of \u03b1-synuclein","volume":"113","author":"C Galvagnion","year":"2016","journal-title":"Proc. Natl. Acad. Sci. U S A"},{"key":"pone.0277602.ref009","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":"B Bembi","year":"2003","journal-title":"Neurology"},{"key":"pone.0277602.ref010","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1002\/(SICI)1096-8652(199907)61:3<216::AID-AJH12>3.0.CO;2-B","article-title":"Parkinson\u2019s syndrome preceding clinical manifestation of Gaucher\u2019s disease.","volume":"61","author":"M Machaczka","year":"1999","journal-title":"Am J Hematol"},{"key":"pone.0277602.ref011","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":"O Neudorfer","year":"1996","journal-title":"QJM"},{"key":"pone.0277602.ref012","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1006\/mgme.2001.3201","article-title":"Gaucher disease and parkinsonism: a phenotypic and genotypic characterization","volume":"73","author":"N Tayebi","year":"2001","journal-title":"Mol Genet Metab"},{"key":"pone.0277602.ref013","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":"E Sidransky","year":"2009","journal-title":"N Engl J Med"},{"key":"pone.0277602.ref014","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1093\/hmg\/ddq454","article-title":"Large-scale screening of the Gaucher\u2019s disease-related glucocerebrosidase gene in Europeans with Parkinson\u2019s disease.","volume":"20","author":"S Lesage","year":"2011","journal-title":"Hum Molec Gen"},{"key":"pone.0277602.ref015","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1016\/j.ymgme.2003.11.004","article-title":"Glucocerebrosidase mutations in subjects with parkinsonism","volume":"81","author":"A Lwin","year":"2004","journal-title":"Mol Genet Metab"},{"key":"pone.0277602.ref016","doi-asserted-by":"crossref","first-page":"1571","DOI":"10.1002\/mds.22538","article-title":"The association between mutations in the lysosomal protein glucocerebrosidase and parkinsonism","volume":"24","author":"J De Paolo","year":"2009","journal-title":"Mov Disord"},{"key":"pone.0277602.ref017","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":"K Wong","year":"2004","journal-title":"Mol Genet Metab"},{"key":"pone.0277602.ref018","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/j.ymgme.2011.06.015","article-title":"\u03b2-Glucocerebrosidase gene mutations in two cohorts of Greek patients with sporadic Parkinson\u2019s disease","volume":"104","author":"M Moraitou","year":"2011","journal-title":"Mol Genet Metab"},{"key":"pone.0277602.ref019","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":"O Goker-Alpan","year":"2010","journal-title":"Acta Neuropathol"},{"key":"pone.0277602.ref020","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/j.ymgme.2011.06.008","article-title":"Aggregation of alpha-synuclein in brain samples from subjects with glucocerebrosidase mutations","volume":"104","author":"JH Choi","year":"2011","journal-title":"Mol Genet Metab"},{"key":"pone.0277602.ref021","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1016\/j.ymgme.2010.12.014","article-title":"Accumulation and distribution of alpha-synuclein and ubiquitin in the CNS of Gaucher disease mouse models","volume":"102","author":"YH Xu","year":"2011","journal-title":"Mol Genet Metab"},{"key":"pone.0277602.ref022","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":"JR Mazzulli","year":"2011","journal-title":"Cell"},{"key":"pone.0277602.ref023","doi-asserted-by":"crossref","first-page":"4028","DOI":"10.1038\/ncomms5028","article-title":"iPSC-derived neurons from GBA1-associated Parkinson\u2019s disease patients show autophagic defects and impaired calcium homeostasis","volume":"14","author":"DC Schondorf","year":"2014","journal-title":"Nat Commun"},{"key":"pone.0277602.ref024","first-page":"2712","article-title":"The contribution of mutant GBA to the development of Parkinson disease in Drosophila","volume":"25","author":"G Maor","year":"2016","journal-title":"Hum Mol Genet"},{"key":"pone.0277602.ref025","doi-asserted-by":"crossref","first-page":"1768","DOI":"10.1093\/hmg\/ddz005","article-title":"The effect of mutant GBA1 on accumulation and aggregation of \u03b1-synuclein","volume":"28","author":"G Maor","year":"2019","journal-title":"Hum Mol Genet"},{"key":"pone.0277602.ref026","first-page":"14","article-title":"Glucocerebrosidase and its relevance to Parkinson disease.","volume":"14","author":"J Do","year":"2019","journal-title":"Mol Neurodegener"},{"key":"pone.0277602.ref027","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1016\/j.bbrc.2007.04.108","article-title":"Expression of \u03b1-synuclein, a presynaptic protein implicated in Parkinson\u2019s disease, in erythropoietic lineage","volume":"358","author":"M Nakai","year":"2007","journal-title":"Biochem Biophys Res Commun"},{"key":"pone.0277602.ref028","doi-asserted-by":"crossref","first-page":"11120","DOI":"10.1038\/srep11120","article-title":"Total and proteinase K-resistant \u03b1-synuclein levels in erythrocytes, determined by their ability to bind phospholipids, associate with Parkinson\u2019s disease.","volume":"5","author":"S Abd-Elhadi","year":"2015","journal-title":"Sci Rep."},{"key":"pone.0277602.ref029","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1016\/j.neulet.2017.11.012","article-title":"\u03b1-Synuclein dimerization in erythrocytes of patients with genetic and non-genetic forms of Parkinson\u2019s disease","volume":"672","author":"N Papagiannakis","year":"2018","journal-title":"Neurosci Lett"},{"key":"pone.0277602.ref030","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/j.neulet.2015.05.030","article-title":"Detection of \u03b1-synuclein oligomers in red blood cells as a potential biomarker of Parkinson\u2019s disease","volume":"599","author":"X Wang","year":"2015","journal-title":"Neurosci Lett"},{"key":"pone.0277602.ref031","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1016\/j.neulet.2012.08.069","article-title":"Increased dimerization of alpha-synuclein in erythrocytes in Gaucher disease and aging","volume":"528","author":"A Argyriou","year":"2012","journal-title":"Neurosci Lett"},{"key":"pone.0277602.ref032","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.neulet.2015.12.013","article-title":"alpha-Synuclein dimerization in erythrocytes of Gaucher disease patients: correlation with lipid abnormalities and oxidative stress","volume":"613","author":"M Moraitou","year":"2016","journal-title":"Neurosci Lett"},{"key":"pone.0277602.ref033","doi-asserted-by":"crossref","first-page":"989","DOI":"10.1002\/mds.26200","article-title":"Plasma oligomeric alpha-synuclein is associated with glucocerebrosidase activity in Gaucher disease","volume":"30","author":"E Nuzhnyi","year":"2015","journal-title":"Mov Disord"},{"key":"pone.0277602.ref034","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1016\/j.neulet.2014.09.041","article-title":"Increased plasma oligomeric alpha-synuclein in patients with lysosomal storage diseases","volume":"583","author":"SN Pchelina","year":"2014","journal-title":"Neurosci Lett"},{"key":"pone.0277602.ref035","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1007\/978-3-540-76698-8_11","volume-title":"Laboratory Guide to the Methods in Biochemical Genetics","author":"M Duran","year":"2008"},{"key":"pone.0277602.ref036","doi-asserted-by":"crossref","first-page":"1856","DOI":"10.1021\/acs.analchem.5b04227","article-title":"Tandem Mass Spectrometry Multiplex Analysis of Glucosylceramide and Galactosylceramide Isoforms in Brain Tissues at Different Stages of Parkinson Disease","volume":"88","author":"M Boutin","year":"2016","journal-title":"Anal Chem"},{"key":"pone.0277602.ref037","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1016\/j.cca.2017.01.014","article-title":"Simultaneous quantitation of sphingoid bases by UPLC-ESI- MS\/MS with identical 13C-encoded internal standards","volume":"466","author":"M Mirzaian","year":"2017","journal-title":"Clin Chim Acta"},{"key":"pone.0277602.ref038","doi-asserted-by":"crossref","first-page":"1851","DOI":"10.1194\/jlr.RA119000154","article-title":"Role of \u03b2-glucosidase 2 in aberrant glycosphingolipid metabolism: model of glucocerebrosidase deficiency in zebrafish","volume":"60","author":"LT Lelieveld","year":"2019","journal-title":"J Lipid Res"},{"key":"pone.0277602.ref039","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1111\/jnc.14968","article-title":"The biochemical basis of interactions between Glucocerebrosidase and alpha-synuclein in GBA1 mutation carriers","volume":"154","author":"M Toffoli","year":"2020","journal-title":"J Neurochem"},{"key":"pone.0277602.ref040","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1159\/000112832","article-title":"Red blood cells are the major source of alpha-synuclein in blood","volume":"5","author":"R Barbour","year":"2008","journal-title":"Neurodegener Dis"},{"key":"pone.0277602.ref041","doi-asserted-by":"crossref","first-page":"1997","DOI":"10.1002\/mds.28688","article-title":"Increased \u03b1-Synuclein Level in CD45+ Blood Cells in Asymptomatic Carriers of GBA Mutations","volume":"36","author":"A Emelyanov","year":"2021","journal-title":"Mov Disord"},{"key":"pone.0277602.ref042","doi-asserted-by":"crossref","first-page":"1267","DOI":"10.1002\/mds.28496","article-title":"Profiling the Biochemical Signature of GBA-Related Parkinson\u2019s Disease in Peripheral Blood Mononuclear Cells","volume":"36","author":"M Avenali","year":"2021","journal-title":"Mov Disord"},{"key":"pone.0277602.ref043","doi-asserted-by":"crossref","first-page":"106534","DOI":"10.1016\/j.bpc.2020.106534","article-title":"The interplay between Glucocerebrosidase, alpha-synuclein and lipids in human models of Parkinson\u2019s disease","volume":"273","author":"SS Mu\u00f1oz","year":"2021","journal-title":"Biophys Chem"},{"key":"pone.0277602.ref044","doi-asserted-by":"crossref","first-page":"9617","DOI":"10.1523\/JNEUROSCI.1525-17.2017","article-title":"Glucosylsphingosine Promotes \u03b1-Synuclein Pathology in Mutant GBA- Associated Parkinson\u2019s Disease","volume":"37","author":"YV Taguchi","year":"2017","journal-title":"J Neurosci"},{"key":"pone.0277602.ref045","doi-asserted-by":"crossref","first-page":"2279","DOI":"10.1016\/j.bpj.2010.07.056","article-title":"Effects of curvature and composition on \u03b1-synuclein binding to lipid vesicles","volume":"99","author":"ER Middleton","year":"2010","journal-title":"Biophys J"},{"key":"pone.0277602.ref046","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/j.neuint.2017.12.014","article-title":"Pathological role of lipid interaction with \u03b1-synuclein in Parkinson\u2019s disease","volume":"119","author":"M Suzuki","year":"2018","journal-title":"Neurochem Int"},{"key":"pone.0277602.ref047","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1194\/jlr.M064923","article-title":"Glucosylated cholesterol in mammalian cells and tissues: formation and degradation by multiple cellular \u03b2-glucosidases","volume":"57","author":"AR Marques","year":"2016","journal-title":"J Lipid Res"},{"key":"pone.0277602.ref048","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1016\/j.bcmd.2014.01.005","article-title":"Gaucher disease: plasmalogen levels in relation to primary lipid abnormalities and oxidative stress","volume":"53","author":"M Moraitou","year":"2014","journal-title":"Blood Cells Mol Dis"},{"key":"pone.0277602.ref049","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 alpha-Synuclein in GBA-N370S Parkinson\u2019s iPSC-Derived Dopamine Neurons","volume":"6","author":"HJ Fernandes","year":"2016","journal-title":"Stem Cell Reports"},{"key":"pone.0277602.ref050","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1111\/j.1365-2141.2010.08214.x","article-title":"Glucocerebrosidase deficiency dramatically impairs human bone marrow haematopoiesis in an in vitro model of Gaucher disease","volume":"150","author":"J Berger","year":"2010","journal-title":"Br J Haematol"},{"key":"pone.0277602.ref051","doi-asserted-by":"crossref","first-page":"546","DOI":"10.1182\/blood-2012-07-442467","article-title":"Abnormal properties of red blood cells suggest a role in the pathophysiology of Gaucher disease","volume":"121","author":"M Franco","year":"2013","journal-title":"Blood"},{"key":"pone.0277602.ref052","doi-asserted-by":"crossref","first-page":"9726","DOI":"10.1111\/jcmm.15534","article-title":"Effects of sphingolipids overload on red blood cell properties in Gaucher disease","volume":"24","author":"L Dupuis","year":"2020","journal-title":"J. Cell Mol. Med"},{"key":"pone.0277602.ref053","doi-asserted-by":"crossref","first-page":"986","DOI":"10.1016\/S1474-4422(12)70190-4","article-title":"The link between the GBA gene and parkinsonism","volume":"11","author":"E Sidransky","year":"2012","journal-title":"Lancet Neurol"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0277602","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,12,6]],"date-time":"2023-12-06T05:50:07Z","timestamp":1701841807000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0277602"}},"subtitle":[],"editor":[{"given":"David","family":"Chau","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2023,2,3]]},"references-count":53,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2023,2,3]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0277602","relation":{},"ISSN":["1932-6203"],"issn-type":[{"type":"electronic","value":"1932-6203"}],"subject":[],"published":{"date-parts":[[2023,2,3]]}}}