Manganese neurotoxicity is a hallmark of Hypermanganesemia with Dystonia 2, an inherited manganese transporter defect caused by mutations in SLC39A14. To identify novel potential targets of manganese neurotoxicity we performed transcriptome analysis of slc39a14−/- mutant zebrafish unexposed and exposed to MnCl2. Differentially expressed genes mapped to the central nervous system and eye, and pathway analysis suggested that calcium dyshomeostasis and activation of the unfolded protein response are key features of manganese neurotoxicity. Consistent with this interpretation, MnCl2 exposure led to decreased whole animal calcium levels, locomotor defects and changes in neuronal activity within the telencephalon and optic tectum. In accordance with reduced tectal activity, slc39a14−/- zebrafish showed changes in visual phototransduction gene expression, absence of visual background adaptation and a diminished optokinetic reflex. Finally, numerous differentially expressed genes in mutant larvae normalised upon MnCl2 treatment indicating that, in addition to neurotoxicity, manganese deficiency is present either subcellularly or in specific cells or tissues. Overall, we assembled a comprehensive set of genes that mediate manganese-systemic responses and found a highly correlated and modulated network associated with calcium dyshomeostasis and cellular stress.
Loss of slc39a14 causes simultaneous manganese hypersensitivity and deficiency in zebrafish
- Award Group:
- Funder(s): Medical Research Council
- Award Id(s): MR/V006754/1
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- Award Group:
- Funder(s): Action Medical Research
- Award Id(s): GN1999
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- Award Group:
- Funder(s): Wellcome Trust
- Award Id(s): 104682/Z/14/Z
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- Award Group:
- Funder(s): Schweizerischer Nationalfonds zur Forderung der Wissenschaftlichen Forschung
- Award Id(s): 31003A_173083
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- Award Group:
- Funder(s): Biotechnology and Biological Sciences Research Council
- Award Id(s): BB/T001844/1
- Funder(s):
- Award Group:
- Funder(s): Comisin Nacional de Investigacin Cient-fica y Tecnologica
- Award Id(s): REDI170300
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Karin Tuschl, Richard J. White, Chintan Trivedi, Leonardo E. Valdivia, Stephanie Niklaus, Isaac H. Bianco, Chris Dadswell, Ramón González-Méndez, Ian M. Sealy, Stephan C. F. Neuhauss, Corinne Houart, Jason Rihel, Stephen W. Wilson, Elisabeth M. Busch-Nentwich; Loss of slc39a14 causes simultaneous manganese hypersensitivity and deficiency in zebrafish. Dis Model Mech 2022; dmm.044594. doi: https://doi.org/10.1242/dmm.044594
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