TY - JOUR
T1 - Expression of the HFE allelic variant H63D in SH-SY5Y cells affects tau phosphorylation at serine residues
AU - Hall, Eric C.
AU - Lee, Sang
AU - Mairuae, Nootchanat
AU - Simmons, Zachary
AU - Connor, James
N1 - Funding Information:
This research was supported by the Harriet H. and Paul G. Campbell Fund for ALS research, ALS Association-Greater Philadelphia Chapter, Zimmerman Love Fund, Jane B. Barsumian Trust Fund, Soter S. and Carolyn C. Harbolis Alzheimer's Research Endowment, and George M. Leader Family.
Copyright:
Copyright 2012 Elsevier B.V., All rights reserved.
PY - 2011/8
Y1 - 2011/8
N2 - 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.
AB - 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.
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U2 - 10.1016/j.neurobiolaging.2009.08.012
DO - 10.1016/j.neurobiolaging.2009.08.012
M3 - Article
C2 - 19775775
AN - SCOPUS:79959590338
SN - 0197-4580
VL - 32
SP - 1409
EP - 1419
JO - Neurobiology of Aging
JF - Neurobiology of Aging
IS - 8
ER -