Expression of the HFE allelic variant H63D in SH-SY5Y cells affects tau phosphorylation at serine residues.
A number of genetic association studies have appeared that address HFE gene variants in neurodegenerative disorders. However, the cellular impact of HFE in the nervous system has received little attention. To begin to address the role of the HFE allelic variants on cellular events associated with neurodegeneration, we examined the hypothesis that HFE polymorphisms are associated with alterations in tau phosphorylation in a human neuroblastoma cell line (SH-SY5Y). The results show that in a cell culture model, the H63D allele is associated with increased tau phosphorylation. The mechanisms responsible for these changes appear related to increased glycogen synthase kinase (GSK)-3β activity. GSK-3β activity is up-regulated in the cells expressing H63D HFE and can be modified by the addition of iron or treatment with an iron chelator in SH-SY5Y cells expressing wild-type HFE. Oxidative stress, also associated with elevated cellular iron, is associated with increased tau phosphorylation at the same sites as seen in H63D cells and treatment with Trolox, an anti-oxidant, lowered tau phosphorylation. These results suggest H63D HFE increases tau phosphorylation via GSK-3β activity and iron-mediated oxidative stress.
George M. Leader Family Laboratory, Department of Neurosurgery, Pennsylvania State University College of Medicine/Milton S. Hershey Medical Center, Hershey, PA 17033, USA.
Eric C
EC
Hall
Sang Y
SY
Lee
Nootchanat
N
Mairuae
Zachary
Z
Simmons
James R
JR
Connor
D000483:Alleles; D000975:Antioxidants / Q000494:pharmacology; D045744:Cell Line, Tumor; D002839:Chromans / Q000494:pharmacology; D014644:Genetic Variation; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism / Q000502:physiology; D000071679:Glycogen Synthase Kinase 3 beta; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D007501:Iron / Q000737:chemistry / Q000502:physiology; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism*; D009447:Neuroblastoma; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D012694:Serine / Q000378:metabolism*; D016875:tau Proteins / Q000378:metabolism*
D000975:Antioxidants; D002839:Chromans; C103673:HFE protein, human; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; D016875:tau Proteins; D012694:Serine; D007501:Iron; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; C010643:6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid