Chemical biology of glucosylceramide metabolism fundamental studies and applications for Gaucher disease

Leiden Repository

Chemical biology of glucosylceramide metabolism fundamental studies and applications for Gaucher disease

Type: Doctoral Thesis
Title: Chemical biology of glucosylceramide metabolism fundamental studies and applications for Gaucher disease
Author: Oussoren, S.V.
Issue Date: 2017-09-28
Keywords: Gaucher disease
Glucocerebrosidase
Cathepsin
LIMP2
Glucosylceramide
Glucosylsphingosine
Activity based probes
Abstract: This thesis describes biochemical investigations of glucocerebrosidase (GBA), the lysosomal β- glucosidase that is deficient in Gaucher disease (GD). Central in the performed research was the examination of factors influencing the intralysosomal stability and half-life of GBA. The investigations made use of new chemical biology tools such as activity based probes (ABPs) and photo-activatable and clickable (PAC) lipids.The Discussion reviews the present insights into GBA in health and disease. In this connection, the molecular basis and clinical manifestation of Gaucher disease and Action Myoclonus Renal Failure syndrome are discussed, including the metabolic adaptations to GBA deficiency. Particular attention is paid to the lysosomal structural stability of GBA and associated resistance against proteolytic degradation by cysteine cathepsins. Literature findings and novel own results on this topic are discussed. New technology to study GBA by labeling with GlcCer and cyclophellitol derived probes is introduced and the application is described. Unresolved research questions on GBA and related disease conditions are identified. As future research objective the translation of fundamental knowledge on GBA to effective therapy of neuronopathic Gaucher disease and other disease conditions caused by enzyme reduction are discussed.
Promotor: Supervisor: J.M.F.G. Aerts Co-Supervisor: R.G. Boot
Faculty: Science
University: Leiden
Handle: http://hdl.handle.net/1887/55842
 

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application/pdf Title page_Table of contents 234.0Kb View/Open
application/pdf General introduction 2.194Mb View/Open
application/pdf Thesis outline 271.5Kb View/Open
application/pdf Chapter 1 1.632Mb Under embargo until 2019-03-28
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application/pdf Chapter 3 1.187Mb Under embargo until 2019-03-28
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application/pdf Discussion 1.307Mb View/Open
application/pdf Addendum 1.230Mb View/Open Full text at publisher site
application/pdf Summary 326.2Kb View/Open
application/pdf Appendices Summ ... lum Vitae_Acknowledgements 428.5Kb View/Open
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