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

Tanara V. Peres, Kyle J. Horning, Julia Bornhorst, Tanja Schwerdtle, Aaron B. Bowman, Michael Aschner

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
JournalBiological Trace Element Research
DOIs
StateAccepted/In press - Jan 1 2018

Fingerprint

Manganese
Toxicity
Molecules
In Vitro Techniques
Dopaminergic Neurons
Caenorhabditis elegans
Nutrition
Dimethyl Sulfoxide
Neurons
Psychiatry
Homeostasis
Throughput

Keywords

  • C. elegans
  • Dopamine
  • Manganese
  • Neurotoxicity
  • Small molecules

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Clinical Biochemistry
  • Inorganic Chemistry
  • Biochemistry, medical

Cite this

Small Molecule Modifiers of In Vitro Manganese Transport Alter Toxicity In Vivo. / Peres, Tanara V.; Horning, Kyle J.; Bornhorst, Julia; Schwerdtle, Tanja; Bowman, Aaron B.; Aschner, Michael.

In: Biological Trace Element Research, 01.01.2018.

Research output: Contribution to journalArticle

Peres, Tanara V. ; Horning, Kyle J. ; Bornhorst, Julia ; Schwerdtle, Tanja ; Bowman, Aaron B. ; Aschner, Michael. / Small Molecule Modifiers of In Vitro Manganese Transport Alter Toxicity In Vivo. In: Biological Trace Element Research. 2018.
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