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| Symbol | IREB2 |
| Full Name |
Iron Responsive Element Binding Protein 2 (IRP2) |
| Chromosome |
15q25.1 |
| NCBI Gene |
3658 |
| Ensembl |
ENSG00000136381 |
| OMIM |
147582 |
| UniProt |
P48200 |
| Protein |
[IRP2 Protein](/proteins/ireb2-protein) |
| Diseases |
[Alzheimer's Disease](/diseases/alzheimers), [Parkinson's Disease](/diseases/parkinsons-disease), NBIA, [ALS](/diseases/als), Neurodegeneration with brain iron accumulation |
| Expression |
[Hippocampus](/brain-regions/hippocampus), Substantia nigra, [Cortex](/brain-regions/cortex), Basal ganglia (enriched in brain) |
| Iron homeostasis, [ferroptosis](/entities/ferroptosis) regulation, IRE-IRP system, oxidative stress, mitochondrial iron metabolism |
IREB2 (Iron Responsive Element Binding Protein 2), encoding IRP2 (Iron Regulatory Protein 2), is the dominant iron-sensing regulatory protein in the mammalian brain. Located on chromosome 15q25.1, IREB2/IRP2 post-transcriptionally controls cellular iron homeostasis by binding to iron-responsive elements (IREs) in the 5' or 3' untranslated regions of mRNAs encoding iron metabolism proteins. IRP2 is the predominant IRP in neurons and is essential for maintaining the delicate balance of iron that is needed for mitochondrial function, neurotransmitter synthesis, and myelination but is toxic when in excess.
Brain iron dysregulation is a central pathogenic mechanism in neurodegeneration. Excessive labile iron catalyzes Fenton chemistry generating hydroxyl radicals and drives ferroptosis — an iron-dependent form of regulated cell death characterized by lipid peroxidation. IRP2 dysfunction has been directly linked to Alzheimer's disease, Parkinson's disease, neurodegeneration with brain iron accumulation (NBIA), and ALS.
The IREB2 gene spans approximately 58 kb on chromosome 15q25.1 and contains 22 exons. The gene encodes a 963-amino acid protein (IRP2, ~105 kDa) that is closely related to IRP1 (ACO1) but lacks aconitase activity. IRP2 contains a unique 73-amino acid domain (exon 5-encoded) that is absent in IRP1 and serves as an iron-dependent degradation signal.
- Iron-dependent regulation: Unlike transcriptional control, IRP2 is primarily regulated post-translationally through iron-dependent proteasomal degradation mediated by FBXL5 (an E3 ubiquitin ligase component)
- Oxygen sensing: IRP2 stability is modulated by oxygen tension, linking iron metabolism to hypoxic responses
- Oxidative stress: ROS stabilize IRP2 by interfering with FBXL5-dependent degradation
- HIF crosstalk: Hypoxia stabilizes IRP2, increasing transferrin receptor expression and iron uptake
IRP2 is the master post-transcriptional regulator of iron metabolism in the brain:
flowchart
A["Diagram needs repair"] --> B["See page content for details"]
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Neuronal iron homeostasis: IRP2 is the predominant IRP in neurons (IRP1 exists primarily as cytoplasmic aconitase in iron-replete conditions). IRP2 knockout mice develop progressive neurodegeneration with iron accumulation in specific brain regions, demonstrating its essential role.
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Mitochondrial iron supply: IRP2 regulates iron availability for mitochondrial electron transport chain complexes and heme biosynthesis. Proper IRP2 function ensures adequate iron for Complex I, Complex II, and Complex IV without allowing toxic iron accumulation.
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Dopamine synthesis: Tyrosine hydroxylase, the rate-limiting enzyme in dopamine synthesis, is iron-dependent. IRP2 regulation of cellular iron directly impacts dopaminergic neuron function and vulnerability.
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Myelination: IRP2 controls iron availability for oligodendrocyte function. Iron is essential for myelin lipid synthesis and maintenance. IRP2 knockout mice show demyelination and axonal degeneration.
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Ferroptosis gatekeeping: By controlling the labile iron pool, IRP2 is a critical upstream regulator of ferroptosis susceptibility. Excess labile iron (from IRP2 dysfunction) catalyzes lipid peroxidation through Fenton reactions, overwhelming GPX4-dependent antioxidant defenses.
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APP processing: IRP2 regulates APP mRNA translation through a 5' IRE in the APP mRNA. Dysregulation of IRP2-dependent APP translation contributes to amyloid pathology.
Iron dysregulation mediated by IRP2 is increasingly recognized as central to AD:
- Iron accumulation in AD brain: Post-mortem AD brains show significant iron accumulation in hippocampus, cortex, and basal ganglia. This correlates with IRP2 dysregulation and exceeds age-related iron increases.
- IRP2 elevation in AD: IRP2 protein levels are paradoxically increased in AD neurons, particularly in hippocampal pyramidal cells bearing neurofibrillary tangles. Elevated IRP2 increases transferrin receptor expression, promoting excessive iron uptake.
- APP IRE regulation: The 5' IRE in APP mRNA means IRP2 directly controls APP translation. IRP2 dysregulation leads to increased APP production and amyloid-β generation.
- Tau iron interaction: Iron promotes tau hyperphosporylation and aggregation. IRP2-mediated iron accumulation accelerates tangle formation and tau-mediated toxicity.
- Ferroptosis in AD: Elevated labile iron from IRP2 dysfunction drives ferroptotic cell death in AD neurons, characterized by lipid peroxidation, GPX4 depletion, and 4-HNE accumulation.
- Ferritin deficit: Despite iron overload, AD neurons show inadequate ferritin (FTH1/FTL) responses, suggesting IRP2 dysfunction prevents appropriate iron storage.
- Substantia nigra iron: The substantia nigra accumulates the highest levels of iron in the brain, and this increases further in PD. IRP2 dysregulation contributes to excessive iron loading of dopaminergic neurons.
- Dopamine-iron oxidative cycle: Iron catalyzes dopamine auto-oxidation, generating reactive quinones and ROS. IRP2-mediated iron excess amplifies this toxic cycle in SN dopaminergic neurons.
- α-Synuclein iron binding: α-Synuclein binds iron and contains a putative IRE-like structure in its 5' UTR, linking IRP2 regulation to synuclein expression and iron-induced aggregation.
- Lewy body iron content: Lewy bodies in PD contain redox-active iron, which drives ongoing lipid peroxidation and oxidative damage in their vicinity.
- Iron chelation therapy: Deferiprone, an iron chelator, has shown benefit in PD clinical trials (FAIR-PARK II), validating iron excess as a therapeutic target.
- IRP2 knockout phenotype: IREB2 knockout mice develop a syndrome resembling NBIA with progressive motor neuron degeneration, axonal degeneration, iron deposition in white matter, and movement abnormalities.
- PANK2: Pantothenate kinase-associated neurodegeneration (PKAN), the most common NBIA, involves disrupted CoA synthesis that secondarily affects IRP2-regulated iron metabolism.
- Related NBIA genes: WDR45, FA2H, COASY, PLA2G6, and FTL mutations cause other NBIA subtypes, all converging on iron dysregulation that IRP2 normally prevents.
- Motor neuron iron: Spinal motor neurons show iron accumulation in ALS. IRP2 dysregulation may contribute to ferroptotic motor neuron death.
- SOD1 and iron: Mutant SOD1 disrupts iron homeostasis and IRP2 regulation, promoting aberrant iron distribution in motor neurons.
IRP2 shows enriched expression in the brain compared to peripheral tissues:
- Hippocampus: Very high expression in CA1 and CA3 pyramidal neurons — the regions most vulnerable in AD
- Substantia nigra: High expression in dopaminergic neurons; increases with aging
- Cortex: Moderate expression across all layers
- Basal ganglia: Strong expression in caudate and putamen
- Cerebellum: Moderate expression in Purkinje cells and deep cerebellar nuclei
- Spinal cord: Expressed in motor neurons
- Oligodendrocytes: Significant expression, supporting iron-dependent myelination
- Microglia: Moderate expression; increases with iron-loaded, activated states
IRP2 expression increases with aging, correlating with age-related brain iron accumulation and increased neurodegenerative disease risk.
- Deferiprone: Blood-brain barrier-permeable iron chelator showing promise in PD (FAIR-PARK II trial) and being explored for AD. Reduces labile iron without depleting functional iron pools.
- Deferoxamine: Showed benefit in early AD trials but poor BBB penetration limits clinical utility. Intranasal delivery is being explored.
- Deferasirox: Oral iron chelator with moderate BBB penetration.
- FBXL5 modulators: Enhancing FBXL5-dependent IRP2 degradation to prevent pathological iron accumulation.
- IRE-targeted therapeutics: Antisense oligonucleotides targeting specific IRE-containing mRNAs to modulate individual iron metabolism genes without disrupting the entire IRP2 system.
- GPX4 activators: Enhancing GPX4 activity to counteract iron-driven lipid peroxidation downstream of IRP2 dysfunction.
- Vitamin E and lipophilic antioxidants: Suppress ferroptotic lipid peroxidation.
- DHODH pathway: Mitochondrial ferroptosis suppressor pathway complementing cytosolic GPX4.
- Ferrostatin-1 and liproxstatin-1: Potent ferroptosis inhibitors in preclinical development.
- LaVaute et al., Targeted deletion of IRP2 causes misregulation of iron metabolism and neurodegeneration (2001)
- Rouault, Iron metabolism in the CNS: implications for neurodegenerative diseases (2013)
- Hentze et al., Two to tango: regulation of mammalian iron metabolism (2010)
- Zecca et al., Iron, brain ageing and neurodegenerative disorders (2004)
- Ayton et al., Brain iron is associated with accelerated cognitive decline in Alzheimer's disease (2020)
- Devos et al., Trial of deferiprone in Parkinson's disease (FAIR-PARK II) (2022)
- Rogers et al., An iron-responsive element in the APP mRNA (2002)
- Stockwell et al., Ferroptosis: a regulated cell death nexus linking metabolism, redox biology, and disease (2017)
- Salahudeen et al., An E3 ligase possessing an iron-responsive hemerythrin domain is a regulator of IRP2 (2009)
- Ward et al., The role of iron in brain ageing and neurodegenerative disorders (2014)