Expression of the neuronal transferrin receptor is age dependent and susceptible to iron deficiency

Moos, Torben; Oates, Phillip S.; Morgan, Evan H.

doi:10.1002/(sici)1096-9861(19980831)398:3<420::aid-cne8>3.0.co;2-1

Cited by 82 publications

(74 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The main players of cellular iron homeostasis comprise: the transferrin receptor (Griffiths and Crossman 1996;Moos et al 1998), the divalent metal transporter DMT1 (Burdo et al 1999(Burdo et al , 2001Williams et al 2000), the iron storage protein ferritin (Benkovic and Connor 1993), and the iron export transporter ferroportin (Wu et al 2004), all of which are well expressed in different areas of the brain. In the particular case of DMT1, which mediates ferrous iron uptake into cells (Gunshin et al 1997), in situ hybridization studies in developing rat brain showed DMT1 mRNA localization in striatum, cortex, hippocampus, and cerebellum (Williams et al 2000).…”

Section: Introductionmentioning

confidence: 99%

Increased Hippocampal Expression of the Divalent Metal Transporter 1 (DMT1) mRNA Variants 1B and +IRE and DMT1 Protein After NMDA-Receptor Stimulation or Spatial Memory Training

et al. 2009

View full text Add to dashboard Cite

Iron is essential for crucial neuronal functions but is also highly toxic in excess. Neurons acquire iron through transferrin receptor-mediated endocytosis and via the divalent metal transporter 1 (DMT1). The N-terminus (1A, 1B) and C-terminus (+IRE, -IRE) splice variants of DMT1 originate four protein isoforms, all of which supply iron to cells. Diverse physiological or pathological conditions induce differential DMT1 variant expression, which are cell-type dependent. Hence, it becomes relevant to ascertain if activation of neuronal plasticity processes that require functional N-methyl D: -aspartate (NMDA) receptors, including in vitro stimulation of NMDA receptor-mediated signaling and spatial memory training, selectively modify DMT1 variant expression. Here, we report for the first time that brief (5 min) exposure of primary hippocampal cultures to NMDA (50 muM) increased 24 h later the expression of DMT1-1B and DMT1+IRE, but not of DMT1-IRE mRNA. In contrast, endogenous DMT1 mRNA levels remained unaffected following 6 h incubation with brain-derived nerve factor. NMDA (25-50 muM) also enhanced DMT1 protein expression 24-48 h later; this enhancement was abolished by the transcription inhibitor actinomycin D and by the NMDA receptor antagonist MK-801, implicating NMDA receptors in de novo DMT1 expression. Additionally, spatial memory training enhanced DMT1-1B and DMT1+IRE expression and increased DMT1 protein content in rat hippocampus, where the exon1A variant was not found. These results suggest that NMDA receptor-dependent plasticity processes stimulate expression of the iron transporter DMT1-1B+IRE isoform, which presumably plays a significant role in hippocampal spatial memory formation.

show abstract

Section: Introductionmentioning

confidence: 99%

Increased Hippocampal Expression of the Divalent Metal Transporter 1 (DMT1) mRNA Variants 1B and +IRE and DMT1 Protein After NMDA-Receptor Stimulation or Spatial Memory Training

et al. 2009

View full text Add to dashboard Cite

show abstract

“…Transferrin receptor (TfR) expression was decreased in the lumbar spinal cords of double transgenic mice from the presymptomatic stage through end-stage. Because TfR is expressed predominantly on neurons [47][48][49], the decrease could reflect the loss of neurons in the SOD1 and double transgenic mice. However, TfR is a cellular iron uptake protein and its expression is post-transcriptionally regulated by cellular iron status.…”

Section: Discussionmentioning

confidence: 99%

H63D HFE genotype accelerates disease progression in animal models of amyotrophic lateral sclerosis

Nandar

Neely

Simmons

et al. 2014

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

View full text Add to dashboard Cite

Keywords:H63D HFE SOD1(G93A) ALS Iron Oxidative stress Gliosis H63D HFE is associated with iron dyshomeostasis and oxidative stress; each of which plays an important role in amyotrophic lateral sclerosis (ALS) pathogenesis. To examine the role of H63D HFE in ALS, we generated a double transgenic mouse line (SOD1/H67D) carrying the H67D HFE (homologue of human H63D) and SOD1(G93A) mutations. We found double transgenic mice have shorter survival and accelerated disease progression. We examined parameters in the lumbar spinal cord of double transgenic mice at 90 days (presymptomatic), 110 days (symptomatic) and end-stage. Transferrin receptor and L-ferritin expression, both indicators of iron status, were altered in double transgenic and SOD1 mice starting at 90 days, indicating loss of iron homeostasis in these mice. However, double transgenic mice had higher L-ferritin expression than SOD1 mice. Double transgenic mice exhibited increased Iba-1 immunoreactivity and caspase-3 levels, indicating increased microglial activation which would be consistent with the higher L-ferritin levels. Although both SOD1 and double transgenic mice had increased GFAP expression, the magnitude of the increase was higher in double transgenic mice at 110 days, suggesting increased gliosis in these mice. Increased hemeoxygenase-1 and decreased nuclear factor E2-related factor 2 levels in double transgenic mice strongly suggest the accelerated disease process could be associated with increased oxidative stress. There was no evidence of TAR-DNA-binding protein 43 mislocalization to the cytoplasm in double transgenic mice; however, there was evidence suggesting neurofilament disruption, which has been reported in ALS. Our findings indicate H63D HFE modifies ALS pathophysiology via pathways involving oxidative stress, gliosis and disruption of cellular functions.

show abstract

“…The receptor is primarily localized to gray matter rather than white matter. Immunoreactivity in neurons is apparent as early as birth and reaches maximal levels at postnatal day 21 (Moos et al, 1998). Oligodendrocytes, which express the highest levels of iron in the brain, may not play a significant role in iron delivery given the preferential distribution of the transferrin receptor in the gray matter (Moos et al, 1998).…”

Section: Transferrinmentioning

confidence: 99%

Heme Regulation in Traumatic Brain Injury: Relevance to the Adult and Developing Brain

Chang

Claus

Vreman

et al. 2005

J Cereb Blood Flow Metab

View full text Add to dashboard Cite

Intracranial bleeding is one of the most prominent aspects in the clinical diagnosis and prognosis of traumatic brain injury (TBI). Substantial amounts of blood products, such as heme, are released because of traumatic subarachnoid hemorrhages, intraparenchymal contusions, and hematomas. Despite this, surprisingly few studies have directly addressed the role of blood products, in particular heme, in the setting of TBI. Heme is degraded by heme oxygenase (HO) into three highly bioactive products: iron, bilirubin, and carbon monoxide. The HO isozymes, in particular HO-1 and HO-2, exhibit significantly different expression patterns and appear to have specific roles after injury. Developmentally, differences between the adult and immature brain have implications for endogenous protection from oxidative stress. The aim of this paper is to review recent advances in the understanding of heme regulation and metabolism after brain injury and its specific relevance to the developing brain. These findings suggest novel clinical therapeutic options for further translational study.

show abstract

Expression of the neuronal transferrin receptor is age dependent and susceptible to iron deficiency

Cited by 82 publications

References 33 publications

Increased Hippocampal Expression of the Divalent Metal Transporter 1 (DMT1) mRNA Variants 1B and +IRE and DMT1 Protein After NMDA-Receptor Stimulation or Spatial Memory Training

Increased Hippocampal Expression of the Divalent Metal Transporter 1 (DMT1) mRNA Variants 1B and +IRE and DMT1 Protein After NMDA-Receptor Stimulation or Spatial Memory Training

H63D HFE genotype accelerates disease progression in animal models of amyotrophic lateral sclerosis

Heme Regulation in Traumatic Brain Injury: Relevance to the Adult and Developing Brain

Contact Info

Product

Resources

About