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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