title: Linking Alpha-Synuclein and the Immune System in the Aetiology of Parkinson's Disease
Creators: name: Parkinson, Rebekah
Publisher: name: The Australian National University
Year: 2025

description: Parkinson's disease, a motor-related neurodegenerative disorder, is characterised by the significant role that a-synuclein and immune activation play in driving disease progression. a-synuclein, an inherent protein prone to misfolding and aggregation is identifed in pathological forms in the central and peripheral nervous system of patients with Parkinson's disease. The immunogenicity of a-synuclein-derived epitopes has been discovered to drive both innate and adaptive immunity in prodromal patients. Despite these findings, the precise mechanistic role of the immune system in contributing to Parkinson's disease remains unclear, largely due to limitations with current animal models. The present study hypothesises that the relationship of a-synuclein and immune activation, as observed in preclinical cases, plays a causal role in Parkinson's disease. To confirm this, Chapter 1 presents the establishment of the first immune-induced murine model of Parkinson's disease whereby immune activation to a-synuclein triggers dopaminergic cell loss and motor deficits. By means of immunising mice to a-synuclein, the model consists of a peripheral injection of a-synuclein protein in adjuvants in wildtype mice. This effectively triggered immune activity identified by raised white blood cell populations, including monocytes, neutrophils, and lymphocytes. alpha-synuclein immunised mice exhibited significant behavioural and neurological alterations compared to control conditions (i.e., sham, and non-injected mice). To discern the trigger of these symptoms, the induction procedure was repeated by injection of a specific alpha-synuclein epitope known to elicit an antigenic response to CD4+ T cells in Parkinson's patients. These mice similarly developed neurological changes in the substantia nigra, including significant decrease of dopaminergic cell density, greater colocalisation of a-synuclein aggregates and increase in proinflammatory cells such as microglia and astrocytes. These changes were supported by levodopa-sensitive deficits in locomotion and gait kinematics. As a dopamine replacement agent, restoration by levodopa supports a Parkinsonian phenotype specific to dopamine loss. The mechanisms underpinning the phenotype of the model are explored in Chapter 2. Specialised analysis of the immunological features in alpha-synuclein immunised mice revealed that CD4+ T cells and neutrophils play a key role in pathogenesis. Induction in a-syn-/- and Rag1-/- (lymphocyte-deficient) mice failed to induce Parkinsons-like symptoms, suggesting that the modelled phenotype is reliant on endogenous a-synuclein and adaptive immune activity. Furthermore, this study posits that an optimal threshold of immune response is required, as neither muted nor boosted immune activation was sufficient to induce or exacerbate symptoms, respectively. In Chapter 3, findings from a cross-sequential analysis of Parkinson's disease patient data supported the hypothesised pathological interplay of immune activation and a-synuclein. Positive correlations were found between a-synuclein seed amplification assays and inflammatory markers in the proteomics and blood chemistry of prodromal Parkinson's disease patients. These immune signatures were observed throughout the disease course and correlated with symptom severity. However, these signatures were uniquely expressed in patients prior to diagnosis suggesting that immune activation is involved in precipitating disease onset. The present study uncovers a causal link between immune cells and a-synuclein in driving Parkinson's disease pathogenesis. This provides the basis for exploring preventative and therapeutic interventions in the first murine immunological model of Parkinson's disease. Ultimately, the model and it's mechanistic insights in early Parkinson's, equips future research with new avenues for the identification of non-invasive Parkinson's disease biomarkers during prodromal stages.