HFE polymorphisms affect cellular glutamate regulation.
HFE gene variants are relatively common genetic variants in Caucasians. The H63D HFE genetic variant has been repeatedly associated with a number of neurodegenerative diseases. We developed neuroblastoma cell lines expressing different HFE polymorphisms to explore the mechanisms behind these associations. Here we tested the hypothesis that cells with the H63D variant have a phenotype that promotes glutamate toxicity. In support of this hypothesis, expression of H63D HFE is associated with increased calcium-induced glutamate secretion and decreased cellular glutamate uptake. The polymorphism-associated changes in glutamate secretion were mimicked by altering cellular iron. Additionally, intracellular calcium is altered in a genotype-specific manner which could further impact glutamate secretion. HFE-dependent effects on glutamate uptake were confirmed in astrocytoma cell lines with endogenous expression of HFE. The ability of minocycline and the antioxidant Trolox to increase glutamate uptake differed by HFE genotype and implicate oxidative stress in glutamate regulation. This study demonstrates HFE cellular effects that extend beyond iron regulation, and suggests that H63D HFE may promote glutamate toxicity.
Mitchell
Ryan M
RM
George M. Leader Family Laboratory, Department of Neurosurgery, Pennsylvania State University College of Medicine/Milton S. Hershey Medical Center, 500 University Drive (H110), Hershey, PA 17033, USA.
Lee
Sang Y
SY
Simmons
Zachary
Z
Connor
James R
JR
D000704:Analysis of Variance; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D003676:Deferoxamine / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005290:Ferric Compounds / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D050491:Glutamate Plasma Membrane Transport Proteins / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism*; D005972:Glutaminase / Q000378:metabolism; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D006801:Humans; D007424:Intracellular Fluid / Q000187:drug effects / Q000378:metabolism; D007501:Iron / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics*; D008911:Minocycline / Q000494:pharmacology; D009447:Neuroblastoma / Q000473:pathology; D011110:Polymorphism, Genetic / Q000235:genetics*; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology; D017262:Siderophores / Q000494:pharmacology; D012964:Sodium / Q000378:metabolism; D013619:Tacrine / Q000494:pharmacology; D014162:Transfection / Q000379:methods; D014316:Tritium / Q000378:metabolism; D050598:Vesicular Glutamate Transport Protein 1 / Q000378:metabolism
D004791:Enzyme Inhibitors; D005290:Ferric Compounds; D050491:Glutamate Plasma Membrane Transport Proteins; C103673:HFE protein, human; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; D000644:Quaternary Ammonium Compounds; D017262:Siderophores; D050598:Vesicular Glutamate Transport Protein 1; D014316:Tritium; D018698:Glutamic Acid; D013619:Tacrine; D012964:Sodium; D007501:Iron; D005972:Glutaminase; D008911:Minocycline; D003676:Deferoxamine; D002118:Calcium; C013531:ferric ammonium citrate