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 30 min followed by co-exposure for 1 h 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.
KeywordsSmall molecules Manganese Neurotoxicity C. elegans Dopamine
MA and ABB were supported by the National Institute of Health (NIH) R01 ES10563 and R01 ES07331. MA was also supported by R01 ES020852. We thank the “Deutsche Forschungsgemeinschaft” (DFG) further for the financial support of Schw 903/9-1 and BO 4103/2-1. Images were obtained at the Analytical Imaging Facility of the Albert Einstein College of Medicine [NCI cancer center support grant (P30CA013330)]. Some strains were provided by the CGC, which is funded by NIH Office of Research Infrastructure Programs (P40 OD010440). Funding agencies had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. In addition, we thank the members of the Vanderbilt Chemical Synthesis Core.
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Conflict of Interest
The authors declare that they have no conflict of interest.
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