Loss of slc39a14 causes simultaneous manganese hypersensitivity and deficiency in zebrafish.
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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 that were exposed to MnCl2. Differentially expressed genes mapped to the central nervous system and eye, and pathway analysis suggested that Ca2+ 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 Ca2+ 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 Ca2+ dyshomeostasis and cellular stress. This article has an associated First Person interview with the first author of the paper.
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Funder: Academy of Medical Sciences; Id: http://dx.doi.org/10.13039/501100000691
Funder: National Institute for Health Research; Id: http://dx.doi.org/10.13039/501100000272
Funder: University College London; Id: http://dx.doi.org/10.13039/501100000765
Funder: Neuroscience Center Zurich, University of Zurich
Funder: Medical Research Council; Id: http://dx.doi.org/10.13039/501100007155
Funder: Wellcome Trust; Id: http://dx.doi.org/10.13039/100010269
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1754-8411
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Great Ormond Street Hospital Charity (V0018)
Medical Research Council (MR/V006754/1, MR/T020164/1, MR/L003775/1)
Fondo Nacional de Desarrollo Científico y Tecnológico (11160951)
Comisión Nacional de Investigación Científica y Tecnológica (REDI170300, REDES170010)
Universidad Mayor (PEP I-2019074)
Wellcome Trust (104682/Z/14/Z, 217150/Z/19/Z)
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (31003A_173083)
Biotechnology and Biological Sciences Research Council (BB/T001844/1)
Wellcome Sanger Institute (WT098051, 206194)