Variabilities in synucleinopathies associated with immune system dysfunction

Parkinson’s disease (PD) and multiple system atrophy (MSA) are progressive neurodegenerative disorders that are collectively referred to as synucleinopathies, due to the presence of α-synuclein inclusions in the brain. Despite similarities between PD and MSA, there is considerable heterogeneity between and within each disorder. This thesis hypothesised that differences in their immune response would relate to differences in their α-synuclein pathologies, and studied demographic, cell and tissue factors that could contribute to such variability.Brain tissue from PD, MSA and control cases was obtained from the New South Wales Brain Banks. Study one assessed the impact of age of onset and disease duration on the cellular localisation and levels of α- and β-synuclein in a number of brain regions using immunohistochemistry and Western blotting. Study two examined the involvement of astrocytes and aquaporin-4 (water channel located on astrocyte endfeet), and study three assessed T lymphocyte infiltration in the same tissue using the same methods. Study four assessed peripheral blood regulatory lymphocyte populations in PD and control donors using flow cytometry.The results of these studies confirm the thesis hypothesis having revealed a number of novel findings distinguishing PD from MSA, and subgroups within PD. Patients with PD onset over 70 years showed increased α-synuclein deposition compared to those with a younger onset, consistent with more severe clinical disease in older onset patients. A massive increase in levels of β-synuclein and evidence of dysregulated astrocytes (together with reduced numbers of aquaporin-4 molecules on astrocyte processes) was observed in the PD putamen, with many of these changes relating to α-synuclein and/or age of onset. Furthermore, a trend towards reduced numbers of regulatory lymphocyte populations was observed in the blood of PD patients, and may have implications for the development of biomarke