This thesis focusses on the further unravelling of one of the mechanisms involved in developing Parkinson's disease: the GBA1 gene, encoding the lysosomal enzyme GCase. Several questions are... Show moreThis thesis focusses on the further unravelling of one of the mechanisms involved in developing Parkinson's disease: the GBA1 gene, encoding the lysosomal enzyme GCase. Several questions are addressed: How prevalent are mutations in this gene in the Netherlands and does it affect disease onset (chapter 2 and 5)? What methodological challenges accompany the sequencing of this gene (chapter 3 and 4)? What biomarkers may be used in clinical trials targeting GCase (chapter 6)? And what are the effects of the novel GCase activator LTI-291, when first administered to healthy volunteers (chapter 7) and to GBA-PD patients (chapter 8)? Show less
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... Show moreThis 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. Show less
