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

Text Devine_10130119_Thesis.pdf Access restricted to UCL open access staff until 1 July 2024. Download (7MB)

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.

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