TY  - JOUR
A1  - Peres, Tanara V.
A1  - Horning, Kyle J.
A1  - Bornhorst, Julia
A1  - Schwerdtle, Tanja
A1  - Bowman, Aaron B.
A1  - Aschner, Michael
T1  - Small Molecule Modifiers of In Vitro Manganese Transport Alter Toxicity In Vivo
T2  - Biological Trace Element Research
N2  - 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 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.
KW  - Small molecules
KW  - Manganese
KW  - Neurotoxicity
KW  - C. elegans
KW  - Dopamine
Y1  - 2018
UR  - https://publishup.uni-potsdam.de/frontdoor/index/index/docId/50094
SN  - 0163-4984
SN  - 1559-0720
VL  - 188
IS  - 1
SP  - 127
EP  - 134
PB  - Human press inc.
CY  - Totowa
ER  -