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Exploring the importance of cell-type-specific gene expression regulation and splicing in Parkinson’s disease

Reynolds, Regina Hertfelder; (2021) Exploring the importance of cell-type-specific gene expression regulation and splicing in Parkinson’s disease. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Parkinson’s disease (PD) is defined primarily as a movement disorder, but its symptoms extend beyond the diagnosis-defining motor symptoms. Among non-motor symptoms, dementia is one of the most common and debilitating, yet it remains relatively understudied in comparison to motor symptoms, in part due to the considerable clinical, genetic and pathologic overlap between Parkinson’s disease with dementia (PDD) and dementia with Lewy bodies (DLB). Common to all three diseases is a lack of disease-modifying therapies, the development of which requires knowledge of the genes, cell types and biological pathways affected in disease. In this thesis, publicly available brain-relevant functional genomic annotations were used to identify PD-relevant pathways and cell types in silico. PD heritability was not found enriched in a specific cell type or state; however, PD heritability was found significantly enriched in a lysosomal and loss-of-function-intolerant gene set, with the former highly expressed in astrocytic, microglial, and oligodendrocyte subtypes and the latter highly expressed in almost all tested cellular subtypes. In addition, new annotations were generated by applying bulk-tissue and single-nucleus RNA-sequencing to anterior cingulate cortex samples derived from individuals with PD, PDD and DLB. This pairing permitted cellular deconvolution of bulk-tissue gene expression; estimation of bulk-tissue cell-type abundances; and in-depth splicing analyses. These analyses found that PD, PDD and DLB were associated not just with one, but several cell types, including neuronal, glial and vascular cell types, suggesting that these are disorders of global pathways working across various cell types. Furthermore, these analyses illustrated the commonalities and differences between the three diseases in terms of associated pathways, cell types, and upstream regulators of splicing, observations that can be used to begin building a biological basis on which to distinguish these disorders.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Exploring the importance of cell-type-specific gene expression regulation and splicing in Parkinson’s disease
Event: UCL
Language: English
Additional information: Copyright © The Author 2021. Original content in this thesis is licensed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) Licence (https://creativecommons.org/licenses/by/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
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 Population Health Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Genetics and Genomic Medicine Dept
URI: https://discovery.ucl.ac.uk/id/eprint/10119171
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