Mutant HFE H63D Protein Is Associated with Prolonged Endoplasmic Reticulum Stress and Increased Neuronal Vulnerability

• DOI: 10.1074/jbc.m110.170944
• Publication Date: 2011-02-25T01:38:11Z
• Authors: Yiting Liu; Sang Y. Lee; Elizabeth Neely; Wint Nandar; Mthabisi Moyo; Zachary Simmons; James R. Connor
• Keywords: ATF6; Mutant protein

A specific polymorphism in the hemochromatosis (HFE) gene, H63D, is over-represented neurodegenerative disorders such as amyotrophic lateral sclerosis and Alzheimer disease. Mutations of HFE are best known being associated with cellular iron overload, but mechanism by which H63D might increase risk neuron degeneration unclear. Here, using an inducible expression cell model developed from a human neuronal line SH-SY5Y, we reported that presence protein activated unfolded response (UPR). This was followed persistent endoplasmic reticulum (ER) stress, signals UPR sensors attenuated up-regulation caspase-3 cleavage activity. Our vitro findings were recapitulated transgenic mouse carrying Hfe H67D, equivalent mutation. In this model, activation detected lumbar spinal cord at 6 months then declined 12 association increased cleavage. Moreover, upon prolonged ER number cells expressing early apoptosis moderately. Cell proliferation decreased without death. Additionally, despite level it appeared stress not responsive to change status. Overall, our studies indicate mutant chronically vulnerability.