{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T22:26:53Z","timestamp":1787005613622,"version":"build-2736575974"},"reference-count":41,"publisher":"Oxford University Press (OUP)","issue":"15","license":[{"start":{"date-parts":[[2023,5,5]],"date-time":"2023-05-05T00:00:00Z","timestamp":1683244800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100019256","name":"NIHR Great Ormond Street Hospital Biomedical Research Centre","doi-asserted-by":"publisher","award":["NIHR203317"],"award-info":[{"award-number":["NIHR203317"]}],"id":[{"id":"10.13039\/501100019256","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,7,20]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Fabry disease stems from a deficiency of alpha-galactosidase and results in the accumulation of globotriaosylceramide (Gb3). However, the production of its deacylated form globotriaosylsphingosine (lyso-Gb3) is also observed and its plasma levels have closer association with disease severity. Studies have shown that lyso-Gb3 directly affects podocytes and causes sensitisation of peripheral nociceptive neurons. However, little is understood of the mechanisms of this cytotoxicity. To study the effect on neuronal cells, we incubated SH-Sy5y cells with lyso-Gb3 at low (20\u00a0ng\/mL) and high (200\u00a0ng\/mL) levels, to mimic mild and classical FD serum levels. We used glucosylsphingosine as a positive control to determine specific effects of lyso-Gb3. Proteomic analyses revealed that cellular systems affected by lyso-Gb3 included cell signalling particularly protein ubiquitination and protein translation. To confirm ER\/proteasome perturbations, we performed an immune enrichment of ubiquitinated proteins and demonstrated specific increased protein ubiquitination at both doses. The most ubiquitinated proteins observed included the chaperone\/heat shock proteins, cytoskeletal proteins and synthesis\/translation proteins. To detect proteins that interact directly with lyso-Gb3, we immobilised lyso-lipids, then incubated them with neuronal cellular extracts and identified bound proteins using mass spectrometry. Proteins that specifically bound were chaperones and included HSP90, HSP60 and the TRiC complex. In conclusion, lyso-Gb3 exposure affects pathways involved in protein translation and folding. This response is observed as increased ubiquitination and changes in signalling proteins which may explain the multiple biological processes, particularly cellular remodelling, often associated with FD.<\/jats:p>","DOI":"10.1093\/hmg\/ddad073","type":"journal-article","created":{"date-parts":[[2023,5,5]],"date-time":"2023-05-05T14:34:29Z","timestamp":1683297269000},"page":"2464-2472","source":"Crossref","is-referenced-by-count":22,"title":["Elucidating the toxic effect and disease mechanisms associated with Lyso-Gb3 in Fabry disease"],"prefix":"10.1093","volume":"32","author":[{"given":"Valeria","family":"Nikolaenko","sequence":"first","affiliation":[{"name":"Genetics & Genomic Medicine Department, Translational Mass Spectrometry Research Group , London WC1N 1EH , UK"},{"name":"Great Ormond Street Hospital Biomedical Research Centre, UCL Institute of Child Health , London WC1N 1EH , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David G","family":"Warnock","sequence":"additional","affiliation":[{"name":"Division of Nephrology, University of Alabama at Birmingham , Birmingham, AL 35298 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin","family":"Mills","sequence":"additional","affiliation":[{"name":"Genetics & Genomic Medicine Department, Translational Mass Spectrometry Research Group , London WC1N 1EH , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wendy E","family":"Heywood","sequence":"additional","affiliation":[{"name":"Genetics & Genomic Medicine Department, Translational Mass Spectrometry Research Group , London WC1N 1EH , UK"},{"name":"Great Ormond Street Hospital Biomedical Research Centre, UCL Institute of Child Health , London WC1N 1EH , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,5,5]]},"reference":[{"key":"2023072112074310600_ref1","doi-asserted-by":"crossref","DOI":"10.1002\/9781119697312","volume-title":"Lysosomal Storage Disorders: A Practical Guide","author":"Mehta","year":"2022"},{"key":"2023072112074310600_ref2","doi-asserted-by":"crossref","first-page":"716","DOI":"10.1002\/1873-3468.12104","article-title":"Lysosomal glycosphingolipid catabolism by acid ceramidase: formation of glycosphingoid bases during deficiency of glycosidases","volume":"590","author":"Ferraz","year":"2016","journal-title":"FEBS Lett."},{"key":"2023072112074310600_ref3","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.ymgme.2016.10.006","article-title":"Plasma LysoGb3: a useful biomarker for the diagnosis and treatment of Fabry disease heterozygotes","volume":"120","author":"Nowak","year":"2017","journal-title":"Mol. 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