Tuschl, K; (2017) Zebrafish disease models to study the pathogenesis of inherited manganese transporter defects and provide a route for drug discovery. Doctoral thesis , UCL (University College London).

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Abstract

Although manganese is required as an essential trace element excessive amounts are neurotoxic and lead to manganism, an extrapyramidal movement disorder associated with deposition of manganese in the basal ganglia. Recently, we have identified the first inborn error of manganese metabolism caused by mutations in SLC30A10, encoding a manganese transporter facilitating biliary manganese excretion. Treatment is limited to chelation therapy with intravenous disodium calcium edetate which is burdensome due to its route of administration and associated with high socioeconomic costs. Whole exome sequencing in patients with inherited hypermanganesaemia and early-onset parkinsonism-dystonia but absent SLC30A10 mutations identified SLC39A14 as a novel disease gene associated with manganese dyshomeostasis. Zebrafish loss-of-function mutants for slc30a10 (slc30a10U800) and slc39a14 (slc39a14U801) were generated using TALEN and CRISPR/Cas9 genome editing technologies in order to model these Mn transporter defects in vivo. Both mutants demonstrate prominent manganese accumulation during larval development. Adult slc39a14U801 mutants show significantly increased brain manganese levels similar to the human phenotype. During larval stages slc39a14U801 mutants display increased sensitivity to manganese toxicity, reduced locomotor activity and visual impairment upon manganese exposure. This phenotype is accompanied by a reduction of tyrosine hydroxylase positive cells in the ventral diencephalon suggesting an involvement of dopaminergic circuits. RNA sequencing further identified genes involved in neurotransmitter release and signalling, phototransduction, circadian clock, and hypoxia inducible factor (HIF) signalling to be affected by manganese dyshomeostasis. In summary, slc30a10U800 and slc39A14U801 zebrafish mutants provide disease models of inherited manganese transporter defects that allow the study of disease mechanisms to identify novel therapeutic targets with the view to improve clinical treatment strategies.

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