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Glucocerebrosidase mutations and the pathogenesis of Parkinson disease

Beavan, MS; (2015) Glucocerebrosidase mutations and the pathogenesis of Parkinson disease. Doctoral thesis , UCL (University College London). Green open access

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Abstract

To date, a mutation of the glucocerebrosidase gene (GBA) is the strongest genetic risk factor associated to Parkinson’s disease (PD). This leads to my prospective cohort study of a GBA mutation positive cohort for early features of PD. This study indicates that as a group, GBA mutation positive individuals show deterioration in clinical markers consistent with the prodrome of PD. I have generated cell culture models from individuals within the clinical cohort studied, in order to delineate the molecular mechanism of mutant GBA to the pathogenesis of PD. My results on skin fibroblast cultures reproduce the glucocerebrosidase enzyme (GCase) enhancement seen from previous studies following treatment with pharmacological chaperone (PC) molecules. These data further provide support for a link between GBA mutations and changes in the autophagic/lysosomal system, which could predispose to neurodegeneration. Due to the limitation of fibroblasts as a model for interrogating the complete pathway in PD, I studied human adipose neural crest stem cell (NCSC) derived dopaminergic (DA) neurons. This model recapitulated the defects identified in the fibroblast model including: reductions in GCase activity and protein level, and lysosomal abnormalities including impairments of autophagy. In addition, reduced GCase was associated with increased α-synuclein (SNCA). PC treatment restored GCase function, upregulated macroautophagy and lead to a reduction in SNCA levels. PC therapy could represent a novel therapeutic approach for PD.

Type: Thesis (Doctoral)
Title: Glucocerebrosidase mutations and the pathogenesis of Parkinson disease
Event: University College London
Open access status: An open access version is available from UCL Discovery
Language: English
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Clinical and Movement Neurosciences
URI: http://discovery.ucl.ac.uk/id/eprint/1470802
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