Browsing by Author "Albaqami, Abdullah"

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The dopaminergic signalling system in the liver fluke, Fasciola hepatica
(Queen University Belfast, 2024-06) Albaqami, Abdullah; Maule, Aaron
Diseases caused by parasitic platyhelminths threaten agricultural and human health. Anthelmintic medications are used to treat these parasites, but increasing treatment resistance and climate change make long-term control difficult. This thesis investigated the involvement of the dopamine (DA) signalling system in liver fluke biology, a generally unknown target system in platyhelminths. In addition to classical dopamine signalling components, studies included polypyrimidine tract-binding proteins (PTBs), recently implicated in the redevelopment of DA neurons in mammals. Publically available omics datasets were used to search for dopamine signalling components and PTBs in flatworm parasites, with a focus on the liver fluke, Fasciola hepatica. In silico identification of DA pathway components across platyhelminths, revealed that the essential components of the dopamine signalling machinery are evolutionarily conserved throughout most platyhelminths, with the exception of cestodes and some monogeneans. In silico methods revealed for the first time in platyhelminths the presence of PTBs with some variability in their consensus signature motifs compared to those seen in mammals. Drug bioassays were used to expose the effects of DA and a dopamine reuptake transporter inhibitor on juvenile F. hepatica. Furthermore, functional genomics in the form of RNA interference (RNAi)-induced gene silencing was combined with an in vitro liver fluke culture system to interrogate gene function. The addition of dopamine and inhibition of dopamine reuptake consistently led to altered motility and growth in juvenile F. hepatica. The silencing of a dopamine synthetic enzyme (aromatic dopamine decarboxylase; FhAADC) and a vesicular monoamine transporter (FhVMAT) reduced both the motility and growth of worms. In contrast, dopamine beta hydroxylase (FhDBH) silencing increased both the motility and growth of worms. Combinatorial RNAi of the three putative FhPTBs severely impaired the motility and growth of juvenile worms, and eventually resulted in the death of juvenile worms, inhibiting neoblast-like cell proliferation as well as negatively impacting nervous system development. This validated the potential of dopamine signalling and PTBs as new flukicide targets and encourages a more focused effort on their exploitation as new drug targets for liver fluke control.
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