TY - JOUR
T1 - Disease-toxicant screen reveals a neuroprotective interaction between Huntington's disease and manganese exposure
AU - Williams, B. Blairanne
AU - Li, Daphne
AU - Wegrzynowicz, Michal
AU - Vadodaria, Bhavin K.
AU - Anderson, Joel G.
AU - Kwakye, Gunnar F.
AU - Aschner, Michael
AU - Erikson, Keith M.
AU - Bowman, Aaron B.
PY - 2010/1
Y1 - 2010/1
N2 - 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.
AB - 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.
KW - Gene-environment Interactions
KW - Huntington's disease
KW - Manganese
KW - Neurodegeneration
KW - Neuroprotection
KW - Neurotoxicity
UR - http://www.scopus.com/inward/record.url?scp=71649110532&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=71649110532&partnerID=8YFLogxK
U2 - 10.1111/j.1471-4159.2009.06445.x
DO - 10.1111/j.1471-4159.2009.06445.x
M3 - Article
C2 - 19845833
AN - SCOPUS:71649110532
SN - 0022-3042
VL - 112
SP - 227
EP - 237
JO - Journal of Neurochemistry
JF - Journal of Neurochemistry
IS - 1
ER -