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Examining the neuroprotective and neurorestorative efficacy of AAV-hGDF5 and AAV-hGDNF in the AAV-αsynuclein rat model of Parkinson’s disease
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Date
2025-09-19
Authors
Wilson, Fionnuala
Journal Title
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Publisher
University College Cork
Published Version
Abstract
Parkinson’s disease (PD) is the second most common neurodegenerative condition worldwide. It is characterised by cardinal motor symptoms which result from the profound loss of dopaminergic neurons in the midbrain, alongside the misfolding and accumulation of the protein α-synuclein into toxic aggregates. There are currently no therapies capable of slowing or stopping disease progression, and current treatments serve only to manage symptoms. Neurotrophic factor (NTF) therapy has been put forward as a potential disease-modifying therapy. NTFs are proteins that promote the survival of neurons in the mature brain and thus, are thought to have significant therapeutic potential in PD. However, all NTF clinical trials conducted over the past two decades have failed to meet their primary endpoints. These trials focused on two particularNTFs, GDNF and Neurturin, which signal through the rearranged during transfection (RET) receptor, which has since been shown to be downregulated in the parkinsonian brain, which may be one potential reason for the failure of these trials.
Since then, research has deviated towards novel NTFs that signal independently of RET. The main objective of this thesis was to investigate the neuroprotective and restorative potential of one such NTF, GDF5, by using a gene therapy approach in in vivo models of PD to examine the therapeutic potential of GDF5 therapy, alone and in combination with GDNF. This thesis also characterised GDF5’s receptor expression and its signalling in the parkinsonian brain.
The main findings from this thesis were: AAV-delivered GDF5 to the striatum was incapable of protecting against α-synuclein-induced degeneration of the dopaminergic nigrostriatal pathway in adult rats in vivo; delayed administration of either AAV-delivered GDF5 or combination delivery of AAV-GDF5 and AAV-GDNF was capable of partially restoring α-synuclein-induced degeneration of nigrostriatal dopaminergic neurons and their axons, and partially rescuing motor deficits in vivo; and combined delivery of AAV-GDF5 and AAV-GDNF did not exert significantly greater effects than AAV-GDF5 alone. Finally, this thesis validated the expression of GDF5’s receptors on human nigral dopaminergic neurons, verified their retained expression in the parkinsonian brain, and showed that BMP-signalling may be reduced in the PD brain.
Taken together, these findings support the further development of GDF5 as a viable therapeutic option for PD, and strengthen the translational potential of GDF5 to the human condition. These results also highlight the potential of combination therapy of different NTFs to confer increased neuroprotection compared to monotherapy.
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Keywords
Parkinson's , Neurotrophic factor , GDF5 , Alpha synuclein , Therapy , Rat
Citation
Wilson, F. 2025. Examining the neuroprotective and neurorestorative efficacy of AAV-hGDF5 and AAV-hGDNF in the AAV-αsynuclein rat model of Parkinson’s disease. PhD Thesis, University College Cork.