Show simple item record

dc.contributor.advisorDowd, Eilís
dc.contributor.authorMulcahy, Pádraig John
dc.description.abstractEven though half a century has passed since the discovery of the efficacy of the dopamine precursor, levodopa, it remains the most effective therapy for the motor symptoms of Parkinson's disease to this day, despite its serious side effects. One factor that is thought to have contributed to the paucity of novel therapies for this condition is the lack of relevant animal models. Since Parkinson's disease is thought to arise from complex interactions between genes and the environment, modelling the condition using relevant genetic and environmental risk factors may yield a more relevant model. Thus, the aim of this body of work was to develop a novel model of Parkinson's disease using the disease-associated pesticide, rotenone, and/or virally-mediated overexpression of the disease-associated protein, alpha-synuclein. This was addressed using three main approaches: 1) direct intracerebral infusion of rotenone alone, 2) systemic administration of rotenone combined with intranigral administration of AAV-alpha-synuclein, and 3) intracerebral infusion of rotenone with intranigral administration of AAV-alpha-synuclein. In all studies, the impact of the insults on motor function, nigrostriatal integrity and alpha-synuclein expression were assessed. The main findings were 1) that intracerebral infusion of rotenone induces motor impairments with nigrostriatal degeneration but without any alpha-synucleinopathy, 2) that systemic administration of rotenone with intranigral infusion of AAV-alpha-synuclein can induce the classical features of Parkinson's disease but is associated with peripheral toxicity, and 3) that sequential intranigral infusion of AAV-alpha-synuclein and rotenone leads to progressive motor dysfunction with nigrostriatal degeneration and alpha-synuclein overexpression. Overall, this research has shown that the sequential intranigral dual-hit model provides a relevant and robust Parkinson's disease model, which, with further validation, may be useful for gaining a greater understanding of the complex gene-environment interactions associated with the disease, and also for assessing novel pharmacological, neuroprotective or neuroreparative treatment approaches.en_US
dc.subjectParkinson's Diseaseen_US
dc.subjectDepartment of Pharmacology & Therapeuticsen_US
dc.subjectSchool of Medicineen_US
dc.titleDevelopment of a dual-hit model of Parkinson's disease by combining environmental and genetic risk factorsen_US
dc.contributor.funderScience Foundation Irelanden_US
dc.local.noteThis thesis sought to examine the link between pesticides and the development of Parkinson's disease, the neurodegenerative disease for which there is currently no cure. It was found that subjects exposed to pesticides displayed Parkinson's-like symptoms and behaviours and that this effect was augmented in those with a genetic predisposition. These findings, that Parkinson's disease onset in a majority of cases, is caused by a combination of environmental insults and genetic factors working in synergy, may play a significant role in the development of more effective drug therapies.en_US

Files in this item

Attribution-NonCommercial-NoDerivs 3.0 Ireland
This item is available under the Attribution-NonCommercial-NoDerivs 3.0 Ireland. No item may be reproduced for commercial purposes. Please refer to the publisher's URL where this is made available, or to notes contained in the item itself. Other terms may apply.

The following license files are associated with this item:


This item appears in the following Collection(s)

Show simple item record