ArticleThe Journal of biological chemistry2011
Mutant HFE H63D protein is associated with prolonged endoplasmic reticulum stress and increased neuronal vulnerability.
Article in The Journal of biological chemistry, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers, 1 of them a synthesis that pooled it.
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Who cites it
26 citing papers in PubMed, 1 synthesis or guideline pooled it, 53 citations in OpenAlex.
- HFE genetic variability and risk of alcoholic liver disease: A meta-analysis.Journal of Huazhong University of Science and Technology. Medical sciences = Hua zhong ke ji da xue xue bao. Yi xue Ying De wen ban = Huazhong keji daxue xuebao. Yixue Yingdewen ban · 2016Pooled it
- The Role of Cytochrome P450 Holoenzyme Metabolism in the Origin of Neuropathologies.International journal of molecular sciences · 2026Review
- An integrative neurogenomics workflow for precision medicine in neurodegenerative disorders.Frontiers in dementia · 2026Article
- Haemochromatosis Genotypes and Incident Dementia in a Prospective Study of Older Adults.Neurology · 2025Article
- Transferrin and H-ferritin involvement in brain iron acquisition during postnatal development: impact of sex and genotype.Journal of neurochemistry · 2020Article
- Article
- Brain iron loading impairs DNA methylation and alters GABAergic function in mice.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2019Article
- Impact of HFE variants and sex in lung cancer.PloS one · 2019Article
- The hemochromatosis protein HFE 20 years later: An emerging role in antigen presentation and in the immune system.Immunity, inflammation and disease · 2017Review
- ERAD defects and the HFE-H63D variant are associated with increased risk of liver damages in Alpha 1-Antitrypsin Deficiency.PloS one · 2017Article
- Reduced white matter MRI transverse relaxation rate in cognitively normal H63D-HFE human carriers and H67D-HFE mice.Brain imaging and behavior · 2016Article
- Iron and Neurodegeneration: Is Ferritinophagy the Link?Molecular neurobiology · 2016Review
- Statins accelerate disease progression and shorten survival in SOD1(G93A) mice.Muscle & nerve · 2016Article
- From adaption to death: endoplasmic reticulum stress as a novel target of selective neurodegeneration?Neural regeneration research · 2015Article
- HFE polymorphisms affect survival of brain tumor patients.Journal of neuro-oncology · 2015Article
- Genetic variant coding for iron regulatory protein HFE contributes to hypertension, the TAMRISK study.Medicine · 2015Article
- Influence of lead on repetitive behavior and dopamine metabolism in a mouse model of iron overload.Toxicological research · 2014Article
- Novel loci affecting iron homeostasis and their effects in individuals at risk for hemochromatosis.Nature communications · 2014Article
- Rotenone induces neurotoxicity through Rac1-dependent activation of NADPH oxidase in SHSY-5Y cells.FEBS letters · 2014Article
- The potential for transition metal-mediated neurodegeneration in amyotrophic lateral sclerosis.Frontiers in aging neuroscience · 2014Review
Corrections and comments
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Authors and funding
7 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
A specific polymorphism in the hemochromatosis (HFE) gene, H63D, is over-represented in neurodegenerative disorders such as amyotrophic lateral sclerosis and Alzheimer disease. Mutations of HFE are best known as being associated with cellular iron overload, but the mechanism by which HFE H63D might increase the risk of neuron degeneration is unclear. Here, using an inducible expression cell model developed from a human neuronal cell line SH-SY5Y, we reported that the presence of the HFE H63D protein activated the unfolded protein response (UPR). This response was followed by a persistent endoplasmic reticulum (ER) stress, as the signals of UPR sensors attenuated and followed by up-regulation of caspase-3 cleavage and activity. Our in vitro findings were recapitulated in a transgenic mouse model carrying Hfe H67D, the mouse equivalent of the human H63D mutation. In this model, UPR activation was detected in the lumbar spinal cord at 6 months then declined at 12 months in association with increased caspase-3 cleavage. Moreover, upon the prolonged ER stress, the number of cells expressing HFE H63D in early apoptosis was increased moderately. Cell proliferation was decreased without increased cell death. Additionally, despite increased iron level in cells carrying HFE H63D, it appeared that ER stress was not responsive to the change of cellular iron status. Overall, our studies indicate that the HFE H63D mutant protein is associated with prolonged ER stress and chronically increased neuronal vulnerability.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.