|
|||||
|
|
Disease-toxicant screen reveals a neuroprotective interaction between Huntington's disease and manganese exposure |
|
| Authors: | B Blairanne Williams†‡§¶ Daphne Li†‡ Michal Wegrzynowicz† Bhavin K Vadodaria†‡ Joel G Anderson Gunnar F Kwakye†‡§¶ Michael Aschner‡§¶†† Keith M Erikson Aaron B Bowman†‡§¶ |
| Institution: | Neuroscience Graduate Program, Vanderbilt University Medical Center, Nashville, Tennessee, USA; Department of Neurology, Vanderbilt University Medical Center, Nashville, Tennessee, USA; Vanderbilt Kennedy Center for Research on Human Development, Vanderbilt University Medical Center, Nashville, Tennessee, USA; Vanderbilt Brain Institute, Vanderbilt University Medical Center, Nashville, Tennessee, USA; Center in Molecular Toxicology, Vanderbilt University Medical Center, Nashville, Tennessee, USA; Department of Nutrition, University of North Carolina at Greensboro, Greensboro, North Carolina, USA; Departments of Pediatrics and Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee, USA |
| Abstract: | Recognizing the similarities between Huntington's disease (HD) pathophysiology and the neurotoxicology of various metals, we hypothesized that they may exhibit disease-toxicant interactions revealing cellular pathways underlying neurodegeneration. Here, we utilize metals and the ST Hdh mouse striatal cell line model of HD to perform a gene–environment interaction screen. We report that striatal cells expressing mutant Huntingtin exhibit elevated sensitivity to cadmium toxicity and resistance to manganese toxicity. This neuroprotective gene–environment interaction with manganese is highly specific, as it does not occur with iron, copper, zinc, cobalt, cadmium, lead, or nickel ions. Analysis of the Akt cell stress signaling pathway showed diminished activation with manganese exposure and elevated activation after cadmium exposure in the mutant cells. Direct examination of intracellular manganese levels found that mutant cells have a significant impairment in manganese accumulation. Furthermore, YAC128Q mice, a HD model, showed decreased total striatal manganese levels following manganese exposure relative to wild-type mice. Thus, this disease-toxicant interaction screen has revealed that expression of mutant Huntingtin results in heightened sensitivity to cadmium neurotoxicity and a selective impairment of manganese accumulation. |
| Keywords: | gene–environment Interactions Huntington's disease manganese neurodegeneration neuroprotection neurotoxicity |