Disease-toxicant screen reveals a neuroprotective interaction between Huntington's disease and manganese exposure.
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 STHdh 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.
Williams
B Blairanne
BB
Neuroscience Graduate Program, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Li
Daphne
D
Wegrzynowicz
Michal
M
Vadodaria
Bhavin K
BK
Anderson
Joel G
JG
Kwakye
Gunnar F
GF
Aschner
Michael
M
Erikson
Keith M
KM
Bowman
Aaron B
AB
D000818:Animals; D002417:Cattle; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000139:chemically induced / Q000235:genetics* / Q000517:prevention & control*; D008345:Manganese / Q000633:toxicity*; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics
C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D008345:Manganese