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Modelling spinal bulbar muscular atrophy using human stem cells and mice

Devine, Helen Elizabeth; (2021) Modelling spinal bulbar muscular atrophy using human stem cells and mice. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

Spinal and bulbar muscular atrophy (SBMA), also known as Kennedy’s Disease, is a slowly progressive neuromuscular disease caused by a trinucleotide CAG repeat expansion in the first exon of the androgen receptor (AR) gene which encodes for the polyglutamine repeat tract within the AR protein. The precise mechanisms of polyQ mediated toxicity in SBMA are complex and are yet to be fully understood. Cell lines and animal models of SBMA have provided key information about development and pathogenic mechanisms in neurodegeneration, however, successful translation to clinical therapeutic interventions has been limited. Further insight into molecular mechanisms of disease is likely to require an integrated approach utilising different models recognising the benefits and limitations of each individual model system. In this Thesis, I use the AR100 mouse model and a new human iPSC model of SBMA patient motor neurons to characterise early pathogenic events in SBMA. Using RNA sequencing and phenotyping assays, I found evidence of transcriptional dysregulation, mitochondrial dysfunction, p53/DNA damage response impairment and premature activation of the cell cycle and cellular senescence in both models of SBMA. Identifying these early disease mechanisms offers potential targets for future clinical treatments. This Thesis also describes the development of a portfolio of public engagement in motor neuron disease and proposes that public engagement should be encouraged for all PhD students.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Modelling spinal bulbar muscular atrophy using human stem cells and mice
Event: UCL (University College London)
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Copyright © The Author 2021. 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
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 > Department of Neuromuscular Diseases
URI: https://discovery.ucl.ac.uk/id/eprint/10130119
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