Brain transcriptome perturbations in the transferrin receptor 2 mutant mouse support the case for brain changes in iron loading disorders, including effects relating to long-term depression and long-term potentiation

Abstract

were increased in all models or decreased in all models). Comparison of the two models of hereditary hemochromatosis, which showed more pronounced changes than the dietary ironsupplemented mice, revealed numerous common molecular effects. Pathway analyses highlighted changes for genes relating to long-term depression (6.8-fold enrichment, p=5.4x10 -7 ) and, to a lesser extent, long-term potentiation (3.7-fold enrichment, p=0.01), with generalized reductions in transcription of key genes from these pathways, which are involved in modulating synaptic strength and efficacy and are essential for memory and learning. The agreement across the models suggests the findings are robust and strengthens previous evidence that iron loading disorders affect the brain. Perturbations of brain phenomena such as long-term depression and long-term potentiation might partly explain neurologic symptoms reported for some hemochromatosis patients.4

Brain iron accumulation affects myelin-related molecular systems implicated in a rare neurogenetic disease family with neuropsychiatric features

“…We and others have investigated the brain iron phenotype of mice with disruption of the Hfe gene ( Hfe − / − ) or the transferrin receptor 2 gene ( Tfr2 mut ), the iron regulatory genes causatively associated with hemochromatosis. 11, 12, 13 However, although these models display chronic systemic iron loading, brain iron content remained unchanged at all ages investigated, 11, 12 as also reported for a related Hfe H67D mutation ‘knock-in' mouse model. 14 …”

“…Ferritin and β-actin protein levels were assessed by western immunoblotting as previously described 12 (see Supplementary Table 1 for antibody details).…”

“…Total RNA was isolated and prepared for microarray as previously described. 11, 12 Microarrays were performed using HumanHT-12 v4 Expression BeadChips (Illumina). Following Cubic Spline normalization in GenomeStudio (Illumina, v2010.3), genes were considered differentially expressed if the fold change of the mean NBIA signal relative to mean control signal was at least 1.5.…”

Aberrations in the Iron Regulatory Gene Signature Are Associated with Decreased Survival in Diffuse Infiltrating Gliomas

“…Similarly, TFR2 is thought to be part of the iron sensing complex that regulates hepcidin [31]. When mutated, it disrupts normal neuronal function in the brain, which could affect the response of normal tissue to neoplastic insult [32]. TFR2 is present in high levels in hepatocellular carcinoma, but there is little evidence for its presence in most cancers [33].…”

Is early-life iron exposure critical in neurodegeneration?

“…The basis of this uncertainty is that neurological sequelae are not a major manifestation of haemochromatosis, in which iron levels rise in peripheral organs as the result of mutations in genes including human haemochromatosis (HFE) and transferrin receptor 2 (TFR2). Some animal studies provide further evidence that the brain is protected (Table 3), but additional preclinical studies of the long-term neurological damage that results from systemic iron burden are needed, as evidence for such effects in humans is accumulating (reviewed elsewhere 46,47 and discussed below).…”