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 several aspects of diagnostic and therapeutic possibilities of mitochondrial function in clinical pharmacological. During several clinical studies in healthy volunteers, pre... Show moreThis thesis describes several aspects of diagnostic and therapeutic possibilities of mitochondrial function in clinical pharmacological. During several clinical studies in healthy volunteers, pre-frail elderly and Huntington’s disease patients, we used phosphorous magnetic resonance spectroscopy as the main method to measure mitochondrial function in vivo. Other in vivo methods included Near Infrared Spectroscopy and the novel Protoporphorin-9 Triplet State Lifetime Technique, besides in vitro ELISA methods to measure activity of separate complexes of the mitochondrial electron transport chain. Using these modalities, we showed mitochondrial dysfunction in pre-frail elderly, emphasizing the importance of an active lifestyle in the prevention of sarcopenia and frailty. Using the mitotoxicity of simvastatin, and its reversibility by ubiquinol, we validated the first proof-of-pharmacology model in healthy volunteers to evaluate efficacy of novel mitochondrial function improving compounds. We also described the importance of measuring (mitochondrial) oxygen consumption as a means to measure mitotoxicity of commonly described medications. Lastly, we evaluated the safety and efficacy of the novel compound SBT-020 in a placebo-controlled, double-blinded, randomized controlled trial in mild to moderate Huntington’s disease patients and compared central to peripheral mitochondrial function for the first time, gaining inside into therapeutic possibilities in this complex and devastating disease. Show less
