- Author
-
D. Herrera Moro Chao
- Title
- Glycosphingolipids and the central regulation of metabolism
- Subtitle
- Sugar analogues as research tools
- Supervisors
- Co-supervisors
-
M.C. van Eijk
R.G. Boot - Award date
- 28 February 2017
- Number of pages
- 277
- ISBN
- 9789491602863
- Document type
- PhD thesis
- Faculty
- Faculty of Medicine (AMC-UvA)
- Abstract
-
This thesis describes different studies using sugar analogues to investigate the impact of glycosphingolipid metabolism, in different brain structures involved in the development of α-synucleinopathies and the control of energy homeostasis. Part I comprises several novel approaches to visualize and manipulate different lysosomal and non-lysosomal glycosidases using activity-based probes (cyclophellitol-epoxide type ABPs) capable of selectively labeling active glucocerebrosidase (GBA) or active GBA and glucocerebrosidase 2 together (cyclophellitol-aziridine type ABPs). Special attention is dedicated to the visualization of active GBA and Galactosylceramidase in the brain, in view of their major role in the development of Gaucher disease and Krabbe disease, respectively. Part 2 investigates the use of sugar analogues as beneficial pharmacological agents for the treatment of obesity and type 2 diabetes. These studies focus on the pleotropic effects of N-(5'-adamantane-1'-yl-methoxy)-pentyl-1-deoxynojirimycin (AMP-DNM) in lean and obese rodents on energy metabolism, with an emphasis on the brain mechanisms involved. Evidence is presented for an endocrine-brain axis mediating the satiety and metabolic effects of AMP-DNM with a major role for the Glucagon-like peptide-1 pathway and taste receptors in the gut. In conclusion, sugar analogues can be useful tools for fundamental research and are meaningful candidate drugs to be applied in the clinic to diagnose lysosomal storage diseases or to treat metabolic syndrome. The major role for the brain in mediating the potent effects of the distinct sugar analogues, indicates that future research should be aimed specifically at brain/periphery interventions to modulate different metabolic needs involved in neuropathy and the control of energy metabolism.
- Persistent Identifier
- https://hdl.handle.net/11245.1/aac27c46-52bb-47da-a179-04de1049806f
- Downloads
-
Thesis (complete)
Front matter
General introduction
Chapter 1: Visualization of active glucocerebrosidase in rodent brain with high spatial resolution following in situ labeling with fluorescent activity based probes
Chapter 2: A specific activity-based probe to monitor GH59 galactosylceramidase – the enzyme deficient in Krabbe disease
Chapter 3: Application of fluorescent β-glucopyranosyl-configured cyclophellitol-aziridines for simultaneous differential fluorescent labeling of β-glucosidases and β-galactosidases
Chapter 4: Investigations on therapeutic glucocerebrosidases through paired detection with fluorescent activity-based probes
Chapter 5: Reducing GBA2 activity ameliorates neuropathology in Niemann Pick type C mice
Chapter 6: Gaucher disease and Fabry disease: new markers and insights in pathophysiology for two distinct glycosphingolipidoses
Chapter 7: Impact of obesity on taste receptor expression in non-gustatory organs: emphasis on hypothalamus and brainstem
Chapter 8: The iminosugar AMP-DNM improves satiety and activates brown adipose tissue through GLP1
General discussion and future perspectives
English Summary | Nederlandse samenvatting
Appendices: PhD portfolio | List of publications | Acknowledgements
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