Toffoli, Marco;
(2022)
Advancing the knowledge on the GBA gene and its role on the pathogenesis of Parkinson disease.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Since its first description in the XIV century, the understanding of Parkinson disease (PD) has advanced significantly. However, a considerable part of its pathogenesis remains elusive, and no disease modifying therapy has been successfully developed yet and partly because of this lack of knowledge. The genetic background of PD is diverse, accounting for both mendelian, familial and sporadic forms of the disease. One of the main contributors to the genetic risk of PD is the GBA gene, which encodes for a lysosomal enzyme and is also linked to Gaucher disease, an autosomal recessive storage disorder. GBA variants are relatively frequent in sporadic PD, making it a promising target for disease modifying therapies. However, the penetrance of GBA variants is low and mostly unexplained, with only a minority of GBA variants carriers developing PD. In addition, the study of GBA is complicated by difficulties in sequencing the gene, due to the presence of a highly homologous pseudogene (GBAP1) in close proximity to GBA. The aim of this PhD research is to study potential modifiers of risk of PD among GBA variant carriers. First, I collaborated in the development of RAPSODI, an online tool to assess and follow-up a cohort of GBA carriers, both with and without PD, and analysed the data produced, showing interesting differences between GBA carriers and non-carries. The main outcome of this preliminary assessment is that GBA carriers with PD have significantly worse motor and non-motor symptoms compared to GBA-negative PD patients. Further, I refined a method to sequence the GBA gene with Oxford Nanopore’s MinION and developed a novel method for detecting reciprocal recombinants between the gene and pseudogene. By applying these tools, I was able to detect complex structural variants that might modify the risk of PD, as well as explore the role of intronic variants in GBA.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Advancing the knowledge on the GBA gene and its role on the pathogenesis of Parkinson disease |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2022. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| UCL classification: | 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 UCL |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10153045 |
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