Date of Award
Doctor of Philosophy
Dr Louise Collins
Prof. Gerard O'Keefe
Dr Caitriona Guinane
Parkinson’s disease is a neurodegenerative disorder, characterised by the progressive degeneration of midbrain dopaminergic neurons, and the intracellular aggregation of the α-synuclein protein in neurons throughout the nervous system. These changes result in the characteristic motor impairments in Parkinson’s disease. Current treatments are solely symptomatic and therefore there is an unmet clinical need to develop new disease-modifying therapies that can alter disease progression. For over 25 years, one proposed experimental therapy has focused on the delivery of proteins called neurotrophic factors to the brain to prevent dopaminergic neuron degeneration. However, to date, clinical trials using the most well-known neurotrophic factors have not met their primary endpoints, likely as a result of the down regulation of their signalling receptor called Ret. Therefore, the aim of this thesis was to investigate the efficacy of two Ret-independent neurotrophic factors called GDF5 and BMP2 using in vitro and in vivo models of PD. The main findings of this thesis were that GDF5 and BMP2 protected dopaminergic neurons and their axons from neurotoxin- and α-synuclein-induced degeneration, which is the protein that accumulates in the brains of people with Parkinson’s disease. Moreover, intranigral delivery of an AAV vector carrying the human GDF5 transgene protected dopaminergic neurons and their terminals from α-synuclein-induced degeneration in vivo. This thesis has also identified two clinically approved drugs that were capable of modulating the signalling pathway used by GDF5 and BMP2 to exert their effects on dopaminergic neurons. These compounds, called Quinacrine and Niclosamide, promoted dopaminergic neuron survival, and protected these neurons from neurotoxin- and α-synuclein-induced axonal degeneration. 2 The wider implications of these findings are that they support the conclusion that neurotrophic factor therapy remains a viable therapeutic approach for patients with PD, and they have identified new therapeutics for the future development of neurotrophic factor therapy in Parkinson’s disease.
Goulding, Susan Rebecca, "Defining the potential of Gene Therapy with Bone Morphogenetic Proteins as a novel therapeutic approach in Parkinson’s disease" (2021). Theses [online].
Available at: https://sword.cit.ie/allthe/28
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