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Small Molecule Modifiers of In Vitro Manganese Transport Alter Toxicity In Vivo

  • Manganese (Mn) is essential for several species and daily requirements are commonly met by an adequate diet. Mn overload may cause motor and psychiatric disturbances and may arise from an impaired or not fully developed excretion system, transporter malfunction and/or exposure to excessive levels of Mn. Therefore, deciphering processes regulating neuronal Mn homeostasis is essential to understand the mechanisms of Mn neurotoxicity. In the present study, we selected two small molecules (with opposing effects on Mn transport) from a previous high throughput screen of 40,167 to test their effects on Mn toxicity parameters in vivo using Caenorhabditis elegans. We pre-exposed worms to VU0063088 and VU0026921 for 30min followed by co-exposure for 1h with Mn and evaluated Mn accumulation, dopaminergic (DAergic) degeneration and worm survival. Control worms were exposed to vehicle (DMSO) and saline only. In pdat-1::GFP worms, with GFP labeled DAergic neurons, we observed a decrease of Mn-induced DAergic degeneration in the presence of bothManganese (Mn) is essential for several species and daily requirements are commonly met by an adequate diet. Mn overload may cause motor and psychiatric disturbances and may arise from an impaired or not fully developed excretion system, transporter malfunction and/or exposure to excessive levels of Mn. Therefore, deciphering processes regulating neuronal Mn homeostasis is essential to understand the mechanisms of Mn neurotoxicity. In the present study, we selected two small molecules (with opposing effects on Mn transport) from a previous high throughput screen of 40,167 to test their effects on Mn toxicity parameters in vivo using Caenorhabditis elegans. We pre-exposed worms to VU0063088 and VU0026921 for 30min followed by co-exposure for 1h with Mn and evaluated Mn accumulation, dopaminergic (DAergic) degeneration and worm survival. Control worms were exposed to vehicle (DMSO) and saline only. In pdat-1::GFP worms, with GFP labeled DAergic neurons, we observed a decrease of Mn-induced DAergic degeneration in the presence of both small molecules. This effect was also observed in an smf-2 knockout strain. SMF-2 is a regulator of Mn transport in the worms and this strain accumulates higher Mn levels. We did not observe improved survival in the presence of small molecules. Our results suggest that both VU0063088 and VU0026921 may modulate Mn levels in the worms through a mechanism that does not require SMF-2 and induce protection against Mn neurotoxicity.show moreshow less

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Author details:Tanara V. PeresORCiD, Kyle J. HorningORCiD, Julia BornhorstORCiDGND, Tanja SchwerdtleORCiDGND, Aaron B. BowmanORCiD, Michael AschnerORCiDGND
DOI:https://doi.org/10.1007/s12011-018-1531-7
ISSN:0163-4984
ISSN:1559-0720
Pubmed ID:https://pubmed.ncbi.nlm.nih.gov/30267310
Title of parent work (English):Biological Trace Element Research
Publisher:Human press inc.
Place of publishing:Totowa
Publication type:Article
Language:English
Date of first publication:2018/09/28
Publication year:2019
Release date:2021/03/26
Tag:C. elegans; Dopamine; Manganese; Neurotoxicity; Small molecules
Volume:188
Issue:1
Number of pages:8
First page:127
Last Page:134
Funding institution:National Institute of Health (NIH)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [R01 ES10563, R01 ES07331]; "Deutsche Forschungsgemeinschaft" (DFG)German Research Foundation (DFG) [Schw 903/9-1, BO 4103/2-1]; NCI cancer center support grantUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Cancer Institute (NCI) [P30CA013330]; NIH Office of Research Infrastructure Programs [P40 OD010440]; [R01 ES020852]
Organizational units:Mathematisch-Naturwissenschaftliche Fakultät / Institut für Ernährungswissenschaft
DDC classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Peer review:Referiert
Publishing method:Open Access / Green Open-Access
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