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2; Potential Implications for the Pathogenesis of Gaucher and Parkinson's Diseases

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2; Potential Implications for the Pathogenesis of Gaucher and Parkinson's Diseases Interplay between Glucocerebrosidase 1 and Glucocerebrosidase 2; potential implications for the pathogenesis of Gaucher and Parkinson's diseases. Derek Gerard Burke UCL Great Ormond Street Institute of Child Health Thesis submitted for the degree of Doctor of Philosophy (PhD) at University College London. 2017 1 I, Derek Gerard Burke confirm that the work presented in this thesis is my own. Where information has been derived from other sources, I confirm that this has been indicated in the thesis. Signed.................................................... Date....................................................... 2 Abstract Gaucher disease (GD) is a lysosomal storage disorder with wide clinical heterogeneity, caused by mutations in the GBA gene leading to low or deficient levels of the lysosomal enzyme Glucocerebrosidase (GBA1). Mutations in GBA1 are also the single most common genetic risk factor for developing Parkinson’s disease (PD). However, the majority of GD patients and carriers do not develop PD, suggesting the possibility of other disease modifying factors. GBA2 is a non- lysosomal enzyme capable of hydrolysing the same substrates as GBA1 and hence may be a potential disease modifying factor. Initially, assays for GBA1 and GBA2 were developed to record the relative activities in a range of tissue types. Marked tissue differences in GBA1 and GBA2 activities were recorded with GBA2 the predominant enzyme in brain. Assessment of GBA1 and GBA2 in GD, PD and dystonia patient leucocytes revealed, as expected, decreased GBA1 activity in GD samples. However, 13% of idiopathic PD and dystonia patients also displayed decreased activity. Leucocyte GBA2 activity was found to be elevated in half of GD patients and in brain from a GD mouse model. One patient with mild GD but profound PD had undetectable GBA2 activity. Cellular models of GBA1 and/or GBA2 inhibition, oxidative stress, and mitochondrial dysfunction were used to further study the interplay between GBA1 and GBA2 using SH-SY5Y cells. Inhibition of GBA1 was not found to be associated with an increase in GBA2 activity or protein expression. Similarly, inhibition of GBA2 was not found to be associated with changes in GBA1 activity. Loss of mitochondrial function or oxidative stress was not found to cause loss of GBA1 activity while GBA1 inhibition did not increase cellular susceptibility to oxidative stress. Measurement of ceramides using mass spectrometry did not reveal any downstream effects of GBA1 or GBA2 inhibition on ceramide levels. 3 Table of Contents Abstract………………………………………………………………………………3 List of Figures……………………………………………………………………...12 List of tables……………………………………………………………………….15 List of abbreviations………………………………………………………………18 Chapter 1 Introduction ......................................................................................... 23 1.1 Lysosomes ................................................................................................... 23 1.2 Lysosomal storage disorders ....................................................................... 23 1.3 Sphingolipidoses .......................................................................................... 24 1.4 Gaucher disease .......................................................................................... 27 1.4.1 Introduction ......................................................................................... 27 1.4.2 GBA1 ..................................................................................................... 27 1.4.3 Clinical presentation ............................................................................ 28 1.4.4 Pathophysiology ................................................................................... 29 1.4.5 Laboratory findings and diagnosis ....................................................... 30 1.4.6 Treatment............................................................................................. 32 1.4.7 Monitoring of treatment ...................................................................... 37 1.4.8 Genetics ................................................................................................ 38 1.4.9 Clinical heterogeneity .......................................................................... 39 1.5 Action myoclonus-renal failure syndrome .................................................. 40 1.6 GBA2 (EC3.2.1.45, GH116) .......................................................................... 41 1.6.1 GBA2 Introduction ............................................................................... 41 1.6.2 GBA2 clinically ...................................................................................... 43 1.7 GBA3 (EC 3.2.1.21)....................................................................................... 46 4 1.8 Mechanism of action of GBA1, 2 & 3 .......................................................... 47 1.9 Parkinson’s disease...................................................................................... 48 1.9.1 Introduction/history ............................................................................. 48 1.9.2 Clinical .................................................................................................. 49 1.9.3 Diagnosis .............................................................................................. 49 1.9.4 Treatment............................................................................................. 50 1.9.5 Causes .................................................................................................. 50 1.10 Gaucher Parkinson’s ................................................................................ 51 1.10.1 Introduction ......................................................................................... 51 1.10.2 Clinical presentation ............................................................................ 53 1.10.3 Pathophysiology ................................................................................... 53 1.10.4 Treatment............................................................................................. 55 1.11 GBA1 association with other movement disorders ................................. 56 1.12 Alzheimer’s disease and GBA1................................................................. 56 1.13 Case study - Atypical parkinsonism with apraxia and supranuclear gaze abnormalities in type 1 Gaucher disease. .............................................................. 57 1.14 Other Lysosomal storage disorders and PD............................................. 59 1.15 Hypotheses .............................................................................................. 60 1.16 Aims ......................................................................................................... 62 Chapter 2 Materials and general methods ........................................................... 63 2.1 Reagents ...................................................................................................... 63 2.2 Samples........................................................................................................ 65 2.3 Plasma and leucocyte preparation. ............................................................. 65 2.4 Prepared Reagents ...................................................................................... 66 2.4.1 Buffers .................................................................................................. 66 2.4.2 0.25M Glycine-NaOH pH10.4 stopping reagent .................................. 67 5 2.4.3 4-methylumbelliferone standard ......................................................... 67 2.5 Lysosomal enzyme assays ........................................................................... 68 2.6 Beta-glucosidase (GBA1, EC 3.2.1.45) ......................................................... 68 2.6.1 Leucocyte GBA1 ................................................................................... 68 2.6.2 Cultured cells GBA1 .............................................................................. 69 2.7 Beta-galactosidase (EC 3.2.1.23) ................................................................. 69 2.7.1 Leucocyte beta-galactosidase .............................................................. 69 2.7.2 Cultured cells beta-galactosidase ........................................................ 70 2.8 Total -hexosaminidase (EC 3.2.1.51) ......................................................... 71 2.8.1 Cultured cells ........................................................................................ 71 2.8.2 Leucocytes ............................................................................................ 71 2.8.3 Plasma total beta-hexosaminidase ...................................................... 71 2.9 Acid -1,4-glucosidase (EC 3.2.1.20) in cultured cells ................................ 72 2.10 Citrate synthase (EC 2.3.3.1) .................................................................... 73 2.11 Total Protein assay ................................................................................... 75 2.12 Cell culture ............................................................................................... 77 2.12.1 SH-SY5Y cells ........................................................................................ 77 2.12.2 Fibroblasts culture................................................................................ 79 2.13 Statistical analysis ...................................................................................
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