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Title: Alpha-synuclein and immune system phenotypes in post-mortem human tissue and two prion-like spreading models of Parkinson's disease
Author: Sanchez Garcia, Sheila
ISNI:       0000 0004 9358 5617
Awarding Body: University of Aberdeen
Current Institution: University of Aberdeen
Date of Award: 2020
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Parkinson ́s disease (PD) is a progressive neurological condition currently affecting about 145000 people in the UK. To this day the cause of sporadic PD remains unknown, with several factors thought to contribute to the disease, including genetic predisposition and environmental and endogenous toxins. In recent years, mounting evidence have linked α-synuclein spreading and neuroinflammation to neuron loss and disease progression in PD. In the present thesis we investigated the role of α-synuclein and the innate and immune systems in two seeding models of PD, as well as, in human post-mortem brain tissue from PD patients. The data indicated that α-synuclein seeding in the SN of mice leads first to an inflammatory response and later to neurodegeneration, which mimics the adaptive and innate immune activation and its correlation with synuclein load found in the PD brains. This α-synuclein induced neurodegeneration resulted in mild motor and social recognitions deficits in the animals. However, differences between models in behavioural performance suggested disparities in the mechanism of neurodegeneration initiated by the synthetic human α-synuclein compared to the human-derived synuclein. Pharmacological treatment with an antibody against tumour necrosis factor-alpha (TNFα) resulted in mild neuroprotective effects evident from decreased neuron loss in the SN, although these preliminary findings need further validation in a study with higher statistical power. Overall, post-mortem tissue data from this study suggests a direct link between αsynuclein uptake and initiation of the inflammatory response, both of which contribute to the neurodegeneration of dopaminergic neurons. Our findings indicate that seeding models may prove an important step forward in the replication of PD in rodents. These novel disease models mimic the aggregation of pathogenic α-synuclein and the progressive neurodegeneration found in PD patients. These characteristics make them a good choice for disease modifying drug development.
Supervisor: Riedel, Gernot ; Platt, Bettina Sponsor: Cunningham Trust
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Parkinson's disease ; Alpha-synuclein ; Immune system