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A combined cellular and bioinformatic approach to investigate RET-dependent and independent neurotrophic factors in models of Parkinson’s disease
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Date
2025-09-04
Authors
Morisho, Jolie Z.
Journal Title
Journal ISSN
Volume Title
Publisher
University College Cork
Published Version
Abstract
Parkinson’s disease is a neurodegenerative disorder characterised by the progressive degeneration of midbrain dopaminergic neurons, driven by the pathological accumulation of α-synuclein protein in neurons throughout the nervous system. This neuronal loss underpins the characteristic motor impairments in Parkinson’s disease. Current treatments are merely symptomatic, failing to address the underlying neurodegeneration. As such, there is a need to develop a disease-modifying therapy that can attenuate or reverse disease progression.
One promising method that has received a considerable amount of attention has focused on the delivery of proteins known as neurotrophic factors to the brain, with the aim of preventing the degeneration of dopaminergic neurons. Despite many showing preclinical promise, their clinical applications have been unsuccessful thus far, with clinical trials failing to meet their primary endpoint. GDNF is the most widely studied neurotrophic factor in Parkinson’s disease. It has been proposed that the downregulation of RET, its primary signalling receptor, may underlie the failure of GDNF clinical trials. Using cellular and bioinformatic approaches, this thesis aimed to investigate the efficacy of GDNF, a RET-dependent neurotrophic factor, and GDF5, a RET-independent neurotrophic factor, in Parkinson’s disease.
The main findings of this thesis were that α-synuclein pathology disrupted GDNF/RET signalling in vitro, attenuating downstream activation of pro-survival pathways while also preserving GDNF’s neurite-promoting effects, possibly via alternative pathways. In contrast, GDF5/Smad signalling remained largely resilient to α-synuclein disruptions in vitro but showed reduced neurite outgrowth abilities. Proteomic analysis revealed broad α-synuclein-driven dysregulation of vital neuronal processes, with GDF5 demonstrating a greater restorative capacity than GDNF, particularly in cytoskeletal regulation.
Together, these findings highlight complementary vulnerabilities of the GDNF/RET and GDF5/Smad pathways and support the development of combined neurotrophic strategies for more effective disease-modifying therapies in Parkinson’s disease.
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Keywords
Parkinson's disease , Neurotrophic factors , Neuroscience
Citation
Morisho, J. Z. 2025. A combined cellular and bioinformatic approach to investigate RET-dependent and independent neurotrophic factors in models of Parkinson’s disease. PhD Thesis, University College Cork.