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

Oussoren, S.V. (2017)

Doctoral Thesis

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.

• Gaucher disease
• Glucocerebrosidase
• Cathepsin
• LIMP2
• Glucosylceramide
• Glucosylsphingosine
• Activity based probes

• All authors: Oussoren, S.V.
• Editor(s): Oussoren S.V.
• Supervisor: Aerts, J.M.F.G.
• Co-supervisor: Boot, R.G.
• Committee: Noteborn, M.H.M.; Meijer, A.H.; Cox, T.M.; Lutgens, E.
• Qualification: Doctor (dr.)
• Awarding Institution: Leiden Institute of Chemistry (LIC), Science, Leiden University
• Date: 2017-09-28