Preclinical Insights In Parkinson's Disease

Abstract

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterised by the loss of dopaminergic neurons and the accumulation of misfolded α-synuclein (α-Syn). Although traditionally considered a disorder of the central nervous system, increasing evidence implicates the gastrointestinal (GI) tract and the microbiota-gut-brain axis in PD pathophysiology. Alterations in gut microbial composition, short-chain fatty acid (SCFA) production, and immune signalling have been associated with PD, suggesting that interactions between the gut microbiota, intestinal immune system, and nervous system may contribute to disease development and progression. However, the underlying mechanisms and translational relevance of these observations remain incompletely understood. This thesis aimed to further investigate the role of gut bacteria and associated inflammatory mechanisms in PD and to identify potential therapeutic targets and suitable preclinical approaches. First, the potential contribution of the microbiota-gut-brain axis to PD was reviewed, with particular attention to microbial metabolites, immune signalling, and potential microbiota-targeted interventions. The role of the SCFA butyrate was subsequently examined, given its important immunomodulatory and gene-regulatory properties and the reported alterations in SCFA-producing bacteria in PD. Next, the role of Toll-like receptor 4 (TLR4), an important mediator of inflammatory signalling, was investigated in an oral pesticide-induced mouse model of PD. Pharmacological inhibition of TLR4 using both a peripherally restricted antagonist and an antagonist capable of reaching the brain showed therapeutic potential, with effects on motor symptoms, neurodegeneration, and GI pathology. The bidirectional nature of the gut-brain axis was further investigated using the 6-hydroxydopamine rat model of PD. Striatal lesions resulted not only in PD-like brain pathology but also in α-Syn pathology and neuroinflammation in the colon, providing evidence for brain-to-gut transmission of pathology in this preclinical model. Finally, a systematic review and meta-analysis was performed to evaluate changes in gut microbiota composition and SCFA production across preclinical PD models and to assess their correspondence with findings from human studies. Collectively, the findings presented in this thesis support a role for interactions between the gut microbiota, immune signalling, and the gut and brain in PD. They provide evidence for both gut-to-brain and brain-to-gut pathological processes and highlight inflammatory pathways and microbial metabolites as potential targets for further investigation. At the same time, the systematic evaluation of preclinical models underscores the importance of model selection and translational considerations when investigating the microbiota-gut-brain axis in PD.