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The study of glycosphingolipids and their role in cell toxicity and neurodegeneration using mass spectrometry

Nikolaenko, Valeria; (2023) The study of glycosphingolipids and their role in cell toxicity and neurodegeneration using mass spectrometry. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

Gaucher disease (GD) is a recessive genetic lysosomal storage disorder caused by a deficiency of the enzyme β-glucosidase. The resultant accumulation of its substrate glucosylceramide (Gb1) leads to an array of diverse pathology associated with GD. Interestingly, heterozygous variants in the GBA gene are the most common risk factor for developing Parkinson’s disease. Glucosylsphingosine (GlcSph) – the deacylated form of Gb1 also accumulates and is a better biomarker of the disease progression and treatment monitoring. GlcSph is known to be toxic to neurons but the mechanisms of its toxicity and how much it contributes to GD pathology are not understood. The primary aim of this thesis was to elucidate potential disease mechanisms and the specific effect of GlcSph in the SH-Sy5y cell model at physiological plasma concentrations observed in moderate and severe Gaucher disease using label-free proteomics methodology. Our findings suggest that GlcSph directly leads to the reduction in the mitochondrial complex I activity and altered protein expression from all other complexes as demonstrated by the proteomic analysis. At the concentration relevant to a severe GD phenotype GlcSph exposure results in reduced ATP production, which is only compensated for by an increase in glycolysis and altered TCA cycle at the concentration observed in a moderate GD phenotype. This may be due to the direct binding of GlcSph to the mitochondrial ADP/ATP translocases SLCA25A5 and SCL25A6 and the complex I stabilising protein prohibitin. GlcSph specifically binds α-tubulin and leads to increased ubiquitination of α and β-tubulin species suggesting altered microtubule dynamics. This could explain altered expression of molecular motors as observed in the proteomic analysis and indicates perturbed cellular trafficking. Finally, increased activity of glutathione reductase confirms GlcSph elicits elevated ROS production leading to ER stress, which subsequently disrupts cellular proteostasis and may explain increased protein ubiquitination.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: The study of glycosphingolipids and their role in cell toxicity and neurodegeneration using mass spectrometry
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Copyright © The Author 2023. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request.
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Genetics and Genomic Medicine Dept
URI: https://discovery.ucl.ac.uk/id/eprint/10169856
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