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Title: Exploration and manipulation of cellular pathways for treatment of neurodegeneration
Author: Fears, Kyle
ISNI:       0000 0004 8500 6400
Awarding Body: Cardiff University
Current Institution: Cardiff University
Date of Award: 2019
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Neurodegenerative disorders such as Huntington's disease (HD) and Parkinson's disease (PD) represent a significant and growing public health crisis. In order to combat these devastating illnesses, we must understand the underlying pathophysiology and develop effective treatments. The aim of Chapter 2 was to establish whether the novel ParkinS65A/S65A knock-in mouse represented a robust model of PD. Despite carrying a mutation analogous to those found in human PD, through extensive behavioural testing it became apparent that the ParkinS65A/S65A mouse did not display a Parkinsonian motor phenotype. Chapter 3 was directed towards optimising a gene therapy approach for PD by using adeno-associated viral vectors (AAVs) co-expressing tyrosine hydroxylase (TH) and GTP cyclohydrolase 1 (GCH1) to produce L-DOPA directly within the striatum of the 6-hydroxydopamine (6-OHDA) model of PD. The efficacy of linker-separated bicistronic AAVs was compared to a reference bicistronic AAV with tandem promoters by using multiple behavioural readouts to assess the extent of functional recovery. No behavioural recovery was observed with any AAV, likely reflecting administration of an insufficient dose. In Chapter 4, the effects of the novel peptide RB5 were assessed in wild-type animals. By increasing extracellular protein kinase (ERK) signalling in the striatum, RB5 could represent a disease-modifying strategy for the treatment of HD. RB5 was unsuccessful in increasing striatal ERK signalling when administered systemically or when constitutively expressed within the striatum. Expression of RB5 did not alter the behaviour of mice compared to control mice expressing green fluorescent protein, but a significant number of animals in both groups displayed substantial expression-related neurodegeneration. The results outlined in these chapters demonstrate the challenging nature of the essential steps towards understanding and treatment of neurodegeneration. Firstly, animal models of disease are an invaluable tool but often do not accurately reflect the human condition. Secondly, the benefit of gene therapy lies within a narrow therapeutic window, with transgene under-expression ineffective and transgene over-expression potentially harmful, necessitating optimisation. Finally, disease-modifying treatments are extremely difficult to formulate and should be extensively characterised in healthy mice before use in disease models.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available