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Lestón Pinilla, L 
ORCID: https://orcid.org/0000-0003-0040-2803,
2023.
Modelling neural interaction, dysfunction and degeneration in Parkinson’s disease.
PhD, Nottingham Trent University.
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Laura Rebeca Leston Pinilla 2023.pdf - Published version Download (12MB) | Preview |
Abstract
Parkinson's disease (PD), the second most prevalent neurodegenerative disorder, is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) of the midbrain, which results in movement impairments. The underlying cause of neuronal degeneration in PD remains poorly understood, but genetic and environmental factors are thought to be contributory factors. The genetic mutations and environmental toxins associated with PD development primarily affect three key pathways: mitochondrial homeostasis, oxidative stress, and protein degradation. These pathways diminish with age, the leading risk factor for PD. Furthermore, ageing can give rise to reduced blood flow to the brain, leading to low oxygen levels (hypoxia). As hypoxia can damage dopaminergic neurons, it is possible that it plays a role in the neurodegenerative process that leads to PD. The cellular response to hypoxia is mainly orchestrated by the Hypoxia-inducible factor 1α (HIF-1α), a transcription factor that coordinates the expression of genes that help cells adapt and survive in hypoxia. Despite the observation that HIF-1α signalling is disrupted in PD patients, the specific pathways involved in this process remain to be determined. In addition, HIF-1α stabilizers have been shown to have neuroprotective effects in animal and cellular models of PD.
This project investigates the interplay between hypoxia/HIF-1α and the genes and pathways involved in PD pathogenesis. We also assessed the protective effect of novel chemical HIF-1α inducers and identified HIF-1α targets in neurodegeneration. This investigation was performed in immortalized cellular models, including neuronal SH-SY5Y and LUHMES cells and astrocytic U-87MG cells.
This research found that HIF-1α stabilisation reduced the protein levels of PD-related PINK1 in neuronal cells. Subsequently, compounds that deregulated mitochondrial function, reactive oxygen species production, and protein degradation impaired HIF-1α stabilization. The protective effect of a range of HIF-1α stabilizing drugs was evaluated with ML228 identified as a compound able to alleviate the consequence of complex 1 impairment in SH-SY5Y. ML228 improved a range of parameters, including cell viability, mitochondrial density, mitochondrial membrane potential, ROS production, autophagy markers, cell cycle distribution, and Ca2+ levels. Finally, we uncovered a set of previously unknown potential HIF-1α targets involved in pathways that are important for neuronal homeostasis and linked to PD.
This constitutes the first comprehensive investigation into the interplay between the response to hypoxia via HIF-1α and PD. Our findings suggest a mechanism by which pathways disrupted in PD can decrease HIF-1α stabilization, possibly leading to an impaired hypoxia response, which has been reported in PD patients. Additionally, our study demonstrates the potential of HIF-1α stabilizing drugs as a therapeutic strategy for PD. Overall, our findings suggest that further research into the role of HIF-1α in PD could lead to new insights into PD pathogenesis and treatment.
| Item Type: | Thesis |
|---|---|
| Creators: | Lestón Pinilla, L. |
| Contributors: | Name Role NTU ID ORCID De Girolamo, L. Thesis supervisor LIF3DEGIRLA UNSPECIFIED |
| Date: | September 2023 |
| Rights: | The copyright in this work is held by the author. You may copy up to 5% of this work for private study, or personal, non-commercial research. Any re-use of the information contained within this document should be fully referenced, quoting the author, title, university, degree level and pagination. Queries or requests for any other use, or if a more substantial copy is required, should be directed to the author. |
| Divisions: | Schools > School of Science and Technology |
| Record created by: | Melissa Cornwell |
| Date Added: | 27 Jan 2025 11:22 |
| Last Modified: | 27 Jan 2025 11:22 |
| URI: | https://irep.ntu.ac.uk/id/eprint/52924 |
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