- Lysosomal glycosidases and glycosphingolipids: New avenues for research
M.C. van Eijk
- Award date
- 8 June 2016
- Number of pages
- Document type
- PhD thesis
- Faculty of Medicine (AMC-UvA)
This thesis describes the development of novel research tools and methods for the study of lysosomal glycosidases and glycosphingolipids. Activity-based probes are demonstrated to be valuable instruments to study the role of these enzymes in health and disease. The improved LC-MS/MS methods with internal isotope-labelled standards described assist the sensitive quantification of the substrates and products of the glycosidases deficient in different lysosomal storage disorders. The combined toolbox has furthermore allowed fundamental studies on the nature and specificity of lyso-glycosphingolipid formation, the role of GBA2 enzymatic activity in NPC neuropathology and the occurrence of glucosyl-cholesterol formed by transglucosylation. The noted induction of specific metabolite changes, as well as the over-expression of Gpnmb, in response to lysosomal glycosphingolipid stress provides new read-outs to capitalize on in future investigations. The added insight in the complex pathophysiological processes in glycosphingolipidoses provided by the employment of these novel tools will hopefully translate to the benefit of patients by rendering more accurate prognostic diagnosis and more effective interventions.
- Author's name on the cover: André R. A. Marques.
Due to copyright reasons, Chapters 2, 6, 10, and 11 have been placed under a permanent embargo.
Chapter 1: A specific activity-based probe to monitor GH59 galactosylceramidase – the enzyme deficient in Krabbe disease (Embargo until 08 June 2018)
Chapter 4: Application of fluorescent β-glucopyranosyl-configured cyclophellitol-aziridines for simultaneous differential labeling of β-glucosidases and β-galactosidases (Embargo until 08 June 2018)
Chapter 5: Activity-based probes for retaining human β-D-galactosidases (Embargo until 08 June 2018)
Chapter 8: Adapting to a deficient glycosphingolipid-degrading lysosomal glycosidase – hypothesis review (Embargo until 08 June 2018)
Chapter 14: On the complexity of single lysosomal defects as highlighted by Niemann-Pick type C disease – review (Embargo until 08 June 2018)
General discussion and perspectives for future research (Embargo until 08 June 2018)
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