Abstract
Ion channels play a vital role in cardiac electrophysiology by coordinating the complex electrochemical ion movements that underly the cardiac action potential. The cardiac action potential is modulated by the autonomic nervous system (ANS). In recent years studies have shown an association between cardiac disease and Parkinson’s disease (PD) where the degeneration of the ANS is prominent. However, the effect of Parkinson’s disease-related ANS degeneration on cardiac tissue has not been investigated. The Ala30Pro (A30P) missense mutation of the alpha-synuclein protein is a genetic risk factor of PD, and it may result in alpha-synucleinopathy, which is the pathological hallmark of PD. This study aimed to investigate the effect of alpha-synucleinopathy on the heart and the cardiac ANS utilising the A30P transgenic PD mice model.</p><p> The first part of the thesis reviews the literature providing an overview on association of cardiovascular features in PD. I focused on assessing the clinical evidence supporting potential electrophysiological alterations and alpha-synucleinopathies in the heart and ANS. The second part of the thesis provides a technical verification for microdissection of murine cardiac stellate ganglia (SG); the dissection method and tissue histology were addressed. Using the dissection method and immunohistochemistry, I report that the A30P transgenic PD mice model recapitulates alpha-synuclein (AS) aggregation in its SG and heart. In the third chapter, the mRNA expression of the heart in A30P mice was investigated with high-throughput RNA sequencing. The RNA sequencing revealed that the A30P mutation resulted in molecular-level alterations in the heart and SG; the differentially expressed genes (DEG) by A30P mutation indicated the pathways related to Parkinson’s disease. Furthermore, the loose patch clamp technique was used to investigate tissue-level sodium and potassium channel properties in the animal model. The loose patch technique was first applied to SG tissue, and the ageing-mediated electrophysiological changes in SG was investigated. Additionally, the effect of extracellular AS was examined using an ex vivo model. The study proved that alpha-synuclein aggregates itself have an inhibitory effect on ventricular tissue current. Finally, the heart of A30P transgenic mice was investigated with the loose patch clamp. It was proven that chronic-intracellular AS may alter the kinetics of channel opening properties in the ventricle ex vivo.</p><p> The results of this study demonstrate that alpha-synuclein mutation can alter cardiac and sympathetic ganglionic tissue at the molecular level, causing phenotypical changes in ventricular ion currents. A technique for dissecting and patch clamping SG was established in the study, which can be employed in future neurocardiac research. Additionally, this is the first electrophysiological study reporting pathological changes in SG and cardiac electrophysiological changes in a PD animal model which strongly supports the presence of electrophysiological changes in the heart of PD. This study contributes to understanding the cardiac pathologies in PD at an ex vivo level and can be utilised in future therapeutic development to alleviate potential cardiac damages in PD.</p>