IREB2 — Iron Responsive Element Binding Protein 2

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IREB2 — Iron Responsive Element Binding Protein 2

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IREB2 — Iron Responsive Element Binding Protein 2

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">IREB2 — Iron Responsive Element Binding Protein 2</th>
</tr>
<tr> [@thompson2011]
<td class="label">Symbol</td> [@kaur2014]
<td><strong>IREB2</strong></td> [@pezzuto2022]
</tr> [@siddiq2015]
<tr>
<td class="label">Full Name</td>
<td>Iron Responsive Element Binding Protein 2 (IRP2)</td>
</tr>
<tr>
<td class="label">Chromosome</td>
<td>15q25.1</td>
</tr>
<tr>
<td class="label">NCBI Gene</td>
<td><a href="https://www.ncbi.nlm.nih.gov/gene/3658" target="_blank">3658</a></td>
</tr>
<tr>
<td class="label">Ensembl</td>
<td><a href="https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000136381" target="_blank">ENSG00000136381</a></td>
</tr>
<tr>
<td class="label">OMIM</td>
<td><a href="https://omim.org/entry/147582" target="_blank">147582</a></td>
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/P48200" target="_blank">P48200</a></td>
</tr>
<tr>
<td class="label">Protein</td>
<td>[IRP2 Protein](/proteins/ireb2-protein)</td>
</tr>
<tr>
<td class="label">Diseases</td>
<td>[Alzheimer's Disease](/diseases/alzheimers), [Parkinson's Disease](/diseases/parkinsons-disease), NBIA, [ALS](/diseases/als), Neurodegeneration with brain iron accumulation</td>
</tr>
<tr>
<td class="label">Expression</td>
<td>[Hippocampus](/brain-regions/hippocampus), Substantia nigra, [Cortex](/brain-regions/cortex), Basal ganglia (enriched in brain)</td>
</tr>
<tr>
<th class="infobox-subheader" colspan="2">Key Pathways</th>
</tr>
<tr>
<td colspan="2" style="font-size:0.85em">Iron homeostasis, [ferroptosis](/entities/ferroptosis) regulation, IRE-IRP system, oxidative stress, mitochondrial iron metabolism</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/alzheimer" style="color:#ef9a9a">Alzheimer</a>, <a href="/wiki/anxiety" style="color:#ef9a9a">Anxiety</a>, <a href="/wiki/cancer" style="color:#ef9a9a">Cancer</a>, <a href="/wiki/dementia" style="color:#ef9a9a">Dementia</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">89 edges</a></td>
</tr>
</table>

IREB2 — Iron Responsive Element Binding Protein 2

Overview

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](/entities/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](/mechanisms/ferroptosis) — an iron-dependent form of regulated cell death characterized by lipid peroxidation. IRP2 dysfunction has been directly linked to [Alzheimer's disease](/diseases/alzheimers-disease), [Parkinson's disease](/diseases/parkinsons-disease), neurodegeneration with brain iron accumulation (NBIA), and [ALS](/diseases/als).

Gene Structure

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](/genes/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.

Regulatory Elements

Iron-dependent regulation: Unlike transcriptional control, IRP2 is primarily regulated post-translationally through iron-dependent proteasomal degradation mediated by [FBXL5](/genes/fbxl5) (an E3 ubiquitin ligase component)
Oxygen sensing: IRP2 stability is modulated by oxygen tension, linking iron metabolism to hypoxic responses
Oxidative stress: [ROS](/entities/reactive-oxygen-species) stabilize IRP2 by interfering with FBXL5-dependent degradation
[HIF](/genes/hif1a) crosstalk: Hypoxia stabilizes IRP2, increasing transferrin receptor expression and iron uptake

Function

The IRE-IRP System

IRP2 is the master post-transcriptional regulator of iron metabolism in the brain:

flowchart TD

Mermaid diagram (expand to render)

Key Functions in the Nervous System

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.

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](/genes/ndufs1), [Complex II](/genes/sdha), and [Complex IV](/genes/cox10) without allowing toxic iron accumulation.

Dopamine synthesis: [Tyrosine hydroxylase](/genes/th), the rate-limiting enzyme in dopamine synthesis, is iron-dependent. IRP2 regulation of cellular iron directly impacts dopaminergic neuron function and vulnerability.

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.

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](/genes/gpx4)-dependent antioxidant defenses.

[APP](/entities/app-protein) processing: IRP2 regulates [APP](/genes/app) mRNA translation through a 5' IRE in the APP mRNA. Dysregulation of IRP2-dependent APP translation contributes to amyloid pathology.

Disease Associations

Alzheimer's Disease

Iron dysregulation mediated by IRP2 is increasingly recognized as central to [AD](/diseases/alzheimers-disease):

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](/proteins/amyloid-beta) generation.
[Tau](/proteins/tau) iron interaction: Iron promotes [tau](/proteins/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](/genes/gpx4) depletion, and 4-HNE accumulation.
Ferritin deficit: Despite iron overload, AD neurons show inadequate ferritin ([FTH1](/genes/fth1)/[FTL](/genes/ftl)) responses, suggesting IRP2 dysfunction prevents appropriate iron storage.

Parkinson's Disease

Substantia nigra iron: The substantia nigra accumulates the highest levels of iron in the brain, and this increases further in [PD](/diseases/parkinsons-disease). 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](/proteins/alpha-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.

Neurodegeneration with Brain Iron Accumulation (NBIA)

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](/genes/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](/genes/wdr45), [FA2H](/genes/fa2h), [COASY](/genes/coasy), [PLA2G6](/genes/pla2g6), and [FTL](/genes/ftl) mutations cause other NBIA subtypes, all converging on iron dysregulation that IRP2 normally prevents.

ALS

Motor neuron iron: Spinal motor neurons show iron accumulation in ALS. IRP2 dysregulation may contribute to ferroptotic motor neuron death.
[SOD1](/entities/sod1) and iron: Mutant SOD1 disrupts iron homeostasis and IRP2 regulation, promoting aberrant iron distribution in motor neurons.

Expression Pattern

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](/cell-types/oligodendrocytes): Significant expression, supporting iron-dependent myelination
[Microglia](/cell-types/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.

Therapeutic Implications

Iron Chelation Approaches

Deferiprone: [Blood-brain barrier](/entities/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.

IRP2-Targeted Strategies

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.

Ferroptosis Inhibitors

[GPX4](/genes/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](/genes/dhodh) pathway: Mitochondrial ferroptosis suppressor pathway complementing cytosolic GPX4.

Ferrostatin-1 and liproxstatin-1: Potent ferroptosis inhibitors in preclinical development.

Key Publications

[LaVaute et al., Targeted deletion of IRP2 causes misregulation of iron metabolism and neurodegeneration (2001)](https://doi.org/10.1038/ng792)

[Rouault, Iron metabolism in the CNS: implications for neurodegenerative diseases (2013)](https://doi.org/10.1038/nrn3453)

[Hentze et al., Two to tango: regulation of mammalian iron metabolism (2010)](https://doi.org/10.1016/j.cell.2010.06.028)

[Zecca et al., Iron, brain ageing and neurodegenerative disorders (2004)](https://doi.org/10.1038/nrn1537)

[Ayton et al., Brain iron is associated with accelerated cognitive decline in Alzheimer's disease (2020)](https://doi.org/10.1038/s41380-019-0375-7)

[Devos et al., Trial of deferiprone in Parkinson's disease (FAIR-PARK II) (2022)](https://doi.org/10.1056/NEJMoa2209254)

[Rogers et al., An iron-responsive element in the APP mRNA (2002)](https://doi.org/10.1074/jbc.M207811200)

[Stockwell et al., Ferroptosis: a regulated cell death nexus linking metabolism, redox biology, and disease (2017)](https://doi.org/10.1016/j.cell.2017.09.021)

[Salahudeen et al., An E3 ligase possessing an iron-responsive hemerythrin domain is a regulator of IRP2 (2009)](https://doi.org/10.1126/science.1176تم326)

[Ward et al., The role of iron in brain ageing and neurodegenerative disorders (2014)](https://doi.org/10.1016/S1474-4422(14)70117-6)

External Links

[NCBI Gene: ireb2](https://www.ncbi.nlm.nih.gov/gene/)
[PubMed: ireb2](https://pubmed.ncbi.nlm.nih.gov/?term=ireb2+neurodegeneration)

References

[Hentze et al., Iron regulatory protein families (2006) (2006)](https://doi.org/10.1016/j.tcm.2006.08.003)

[Kumar et al., IRP2 regulates cellular iron homeostasis (2019) (2019)](https://doi.org/10.1002/hep.30698)

[Unknown, Rouault, Iron metabolism in the brain (2006) (2006)](https://doi.org/10.1038/nrn1874)

[Muckenthaler et al., Systemic iron homeostasis (2008) (2008)](https://doi.org/10.1152/physrev.00012.2007)

[Thompson et al., Iron dysregulation in neurodegenerative diseases (2011) (2011)](https://doi.org/10.1016/j.neurobiolaging.2010.09.030)

[Kaur et al., IREB2 and iron metabolism in AD (2014) (2014)](https://doi.org/10.3233/JAD-132765)

[Pezzuto et al., Iron-responsive element binding protein 2 in neurodegeneration (2022) (2022)](https://doi.org/10.1007/s12017-021-08680-w)

[Siddiq et al., IREB2-mediated iron dysregulation in Parkinson's disease (2015) (2015)](https://doi.org/10.1002/mds.26162)

Pathway Diagram

The following diagram shows the key molecular relationships involving IREB2 — Iron Responsive Element Binding Protein 2 discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

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IREB2 — Iron Responsive Element Binding Protein 2

IREB2 — Iron Responsive Element Binding Protein 2

IREB2 — Iron Responsive Element Binding Protein 2

IREB2 — Iron Responsive Element Binding Protein 2

Overview

Gene Structure

Regulatory Elements

Function

The IRE-IRP System

Key Functions in the Nervous System

Disease Associations

Alzheimer's Disease

Parkinson's Disease

Neurodegeneration with Brain Iron Accumulation (NBIA)

ALS

Expression Pattern

Therapeutic Implications

Iron Chelation Approaches

IRP2-Targeted Strategies

Ferroptosis Inhibitors

Key Publications

See Also

External Links

References

Pathway Diagram