SLC40A1 Gene

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gene1638 wordssynced 2026-04-02

SLC40A1 Gene

Introduction

Slc40A1 Gene is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.

Solute Carrier Family 40 Member 1 (Ferroportin) [@quadri2012]

<div class="infobox infobox-gene"> [@chen2019]
<table> [@ward2014]
<tr><th>Gene Symbol</th><td>SLC40A1</td></tr>
<tr><th>Full Name</th><td>Solute Carrier Family 40 Member 1 (Ferroportin)</td></tr>
<tr><th>Chromosomal Location</th><td>2q32.2</td></tr>
<tr><th>NCBI Gene ID</th><td>30061</td></tr>
<tr><th>OMIM</th><td>604653</td></tr>
<tr><th>Ensembl ID</th><td>ENSG00000138448</td></tr>
<tr><th>UniProt ID</th><td>Q9NP59</td></tr>
<tr><th>Associated Diseases</th><td>Neurodegeneration with Brain Iron Accumulation (NBIA), Type IV (Ferroportin Disease), Alzheimer's Disease, Parkinson's Disease</td></tr>
</table>
</div>

Overview

...

SLC40A1 Gene

Introduction

Slc40A1 Gene is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.

Solute Carrier Family 40 Member 1 (Ferroportin) [@quadri2012]

Overview

Mermaid diagram (expand to render)

SLC40A1 Gene is involved in biological pathways relevant to neurodegenerative diseases. It plays important roles in neuronal function, cellular signaling, or stress response mechanisms.

Dysregulation or mutations in this gene/protein contribute to the pathogenesis of Alzheimer's disease, Parkinson's disease, and related neurodegenerative disorders.

Function

SLC40A1 encodes ferroportin, the only known iron exporter in mammals. This protein is essential for iron homeostasis and is expressed in cells that export iron, including macrophages, hepatocytes, and enterocytes.

Key functions include:

Iron export: Ferroportin exports iron from cells into the plasma
Systemic iron regulation: Controls iron entry into circulation from gut, liver, and spleen
[Ferroptosis](/entities/ferroptosis) regulation: Involved in iron-dependent cell death pathways
Hepcidin receptor: Ferroportin is the target of hepcidin, the iron regulatory hormone
Cellular iron homeostasis: Prevents iron accumulation in macrophages and other cells

Ferroportin is a multipass transmembrane protein with 12 transmembrane domains. It exports Fe2+ iron, which is then oxidized to Fe3+ by hephaestin for transferrin binding.

Disease Associations

Neurodegeneration with Brain Iron Accumulation (NBIA) Type IV

SLC40A1 mutations cause a form of NBIA:

Iron overload: Mutations lead to iron accumulation in the brain, particularly in the globus pallidus
Motor symptoms: Patients present with progressive dystonia, parkinsonism, and gait disturbance
Cognitive decline: Some patients develop cognitive impairment
MRI findings: T2 hypointensity in basal ganglia indicating iron deposition

Mutations can be gain-of-function (leading to iron retention) or loss-of-function (causing iron overload syndrome similar to hemochromatosis).

Ferroportin Disease

Heterozygous SLC40A1 mutations cause ferroportin disease:

Iron retention: Macrophages retain iron (ferroportin-high phenotype)
Elevated ferritin: High serum ferritin with normal transferrin saturation
Liver involvement: Iron deposition in liver hepatocytes
Atypical presentation: Differs from classic hemochromatosis

Alzheimer's Disease

Ferroportin dysfunction may contribute to AD:

Brain iron dysregulation: Iron accumulation in AD brain regions
Ferroptosis: Iron-dependent cell death may contribute to neuronal loss
Amyloid interaction: Iron can catalyze [Aβ](/proteins/amyloid-beta) aggregation
Oxidative stress: Iron promotes [ROS](/entities/reactive-oxygen-species) generation

Parkinson's Disease

Iron metabolism is altered in PD:

Substantia nigra iron: Elevated iron in PD substantia nigra
Ferroportin expression: Altered ferroportin in PD brain
Dopaminergic neurons: Iron may promote dopaminergic neuron loss

Expression

SLC40A1 shows cell-type specific expression [@matsu2019]:

Macrophages: High expression in splenic, hepatic, and bone marrow macrophages
Enterocytes: Expression in duodenal enterocytes for dietary iron absorption
Hepatocytes: Expresses ferroportin for iron release into circulation
[Neurons](/entities/neurons): Low basal expression in neurons
[Microglia](/entities/microglia): Expressed in brain [microglia](/cell-types/microglia-neuroinflammation)

Expression is regulated by iron levels and hepcidin (which causes ferroportin internalization and degradation).

Iron Export Mechanism: Detailed Molecular Analysis

Ferroportin Structure and Function

Ferroportin is a unique iron exporter with distinct structural features [@drakesmith2015]:

Protein architecture:

12 transmembrane domains
Multiple iron-binding sites
Basolateral (systemic) localization in polarized cells

Iron export process:

Exports Fe²⁺ (ferrous iron)
Oxidation to Fe³⁺ by hephaestin (intestinal) or ceruloplasmin (other tissues)
Transferrin binding for systemic transport
Rate-limiting step in iron export

Regulation by hepcidin [@ganz2013]:

Hepcidin binds to ferroportin extracellular loop
Induces ferroportin internalization and degradation
Reduces iron export when body iron is high
Loss of function when hepcidin is elevated

Cellular Iron Homeostasis

Ferroportin is central to cellular iron balance:

| Cell Type | Role | Regulation |
|-----------|------|------------|
| Enterocytes | Dietary iron absorption | Ferroxidase activity |
| Hepatocytes | Plasma iron supply | Iron stores |
| Macrophages | Iron recycling | Erythropoietic demand |
| Neurons | Brain iron supply | Local regulation |
| Microglia | Immune cell iron | Inflammatory signals |

Brain Iron Metabolism

Iron in the Central Nervous System

The brain has specialized iron handling mechanisms [@anderson2012] [@pinero2019]:

Blood-brain barrier iron transport:

Transferrin receptor-mediated endocytosis
DMT1 (divalent metal transporter 1) for Fe²⁺ entry
Limited ferroportin expression at BBB

Neuronal iron import:

Transferrin-bound iron uptake via TfR1/TfR2
DMT1 for intracellular iron release
Limited export capacity in neurons

Glial iron handling:

Oligodendrocytes: High iron storage capacity
Astrocytes: Iron buffer function
Microglia: Iron handling in inflammation

Ferroportin in the Brain

Brain-specific ferroportin expression [@matsu2019] [@dmitriev2019]:

Neurons: Low baseline expression, upregulates under iron overload
Astrocytes: Moderate expression, role in iron buffering
Microglia: Inducible expression during inflammation
Endothelial cells: Limited BBB expression
Oligodendrocytes: Important for myelin iron supply

Disease Mechanisms in Detail

Neurodegeneration with Brain Iron Accumulation (NBIA) Type IV

SLC40A1 mutations cause a distinctive form of NBIA [@quadri2012] [@barton2019]:

Pathogenesis:

Gain-of-function mutations: Lead to iron retention (ferroportin resistance to hepcidin)
Loss-of-function mutations: Cause iron overload syndrome similar to hemochromatosis
Both mechanisms lead to brain iron accumulation

Clinical Presentation:

Onset: Typically childhood or early adulthood
Motor symptoms: Progressive dystonia, parkinsonism, gait disturbance
Cognitive decline: Variable, from mild impairment to dementia
MRI findings: T2 hypointensity in globus pallidus, "eye-of-the-tiger" sign

Genotype-phenotype correlations:
| Mutation Type | Phenotype | Iron Pattern |
|---------------|-----------|---------------|
| Gain-of-function | NBIA Type IV | Brain iron accumulation |
| Loss-of-function | Ferroportin disease | Systemic iron overload |

Ferroportin Disease

Hereditary ferroportin disease caused by SLC40A1 mutations [@pelizzo2018]:

Type A (loss-of-function):

Macrophage iron retention
High ferritin, normal transferrin saturation
Aceruloplasminemia-like phenotype

Type B (gain-of-function):

Hepcidin-resistant ferroportin
Elevated transferrin saturation
Classic hemochromatosis phenotype

Alzheimer's Disease

Ferroportin dysfunction contributes to AD pathogenesis [@chen2020]:

Brain iron dysregulation:

Iron accumulation in AD brain regions (frontal cortex, hippocampus)
Elevated ferritin in cerebrospinal fluid
Altered iron regulatory proteins

Ferroptosis mechanism:

Iron-dependent cell death pathway
Lipid peroxidation in neurons
GPX4 downregulation in AD brain

Amyloid interaction:

Iron catalyzes Aβ aggregation
Aβ co-localizes with iron in plaques
Iron promotes oxidative stress

Therapeutic implications:

Iron chelation approaches under investigation
Ferroportin modulators as potential treatment
Antioxidant strategies targeting iron

Parkinson's Disease

Iron metabolism alterations in PD [@li2021]:

Substantia nigra iron:

Markedly elevated iron in PD substantia nigra
Especially in dopaminergic neurons
Correlation with disease severity

Ferroportin expression:

Reduced ferroportin in PD brain
Altered hepcidin/ferroportin axis
Dysregulated iron export

Dopaminergic neuron vulnerability:

Iron promotes dopaminergic neuron loss
Oxidative stress contribution
Mitochondrial dysfunction

Therapeutic targets:

Iron chelation (deferoxamine, deferasirox)
Ferroportin activators
Antioxidant approaches

Neuroinflammation and Ferroportin

Ferroportin plays a role in neuroimmune interactions [@dmitriev2019]:

Microglial iron handling:

Activated microglia accumulate iron
Ferroportin upregulation in inflammation
Altered iron release affects neurons

Inflammatory signaling:

IL-6 modulates ferroportin expression
LPS reduces ferroportin in macrophages
TNF-α affects neuronal iron homeostasis

Iron and neuroinflammation:

Iron promotes microglial activation
Reactive oxygen species generation
Cycle of inflammation and iron dysregulation

Therapeutic Approaches

Targeting Ferroportin

Multiple therapeutic strategies are being developed:

| Approach | Status | Mechanism |
|----------|--------|-----------|
| Hepcidin antagonists | Preclinical | Restore ferroportin function |
| Ferroportin agonists | Discovery | Increase iron export |
| Iron chelators | Clinical | Reduce iron burden |
| Gene therapy | Research | Deliver functional SLC40A1 |

Iron Chelation Therapy

Current chelation approaches for NBIA and related disorders:

Deferoxamine: Subcutaneous administration, limited CNS penetration
Deferasirox: Oral, moderate CNS penetration
Deferiprone: Can cross BBB, being investigated for neurodegeneration
Novel chelators: Brain-penetrant compounds in development

Gene Therapy Considerations

Viral vectors: AAV for CNS delivery
Target cells: Neurons, astrocytes, microglia
Challenges: Appropriate expression levels, regulation

Cross-Linking

[Alzheimer's Disease](/diseases/alzheimers-disease) — AD overview
[Parkinson's Disease](/diseases/parkinsons-disease) — PD overview
[Neurodegeneration with Brain Iron Accumulation (NBIA)](/diseases/nbia) — NBIA disorders
[Iron Metabolism](/experiments/astrocyte-ferritin-iron-metabolism-pd) — Experimental systems
[Ferroptosis](/entities/ferroptosis) — Iron-dependent cell death
[TF Gene](/genes/tf) — Transferrin
[FTH1 Gene](/genes/fth1) — Ferritin heavy chain
[FTL Gene](/genes/ftl) — Ferritin light chain
[Heph Gene](/genes/heph) — Hephaestin
[CP Gene](/genes/cp) — Ceruloplasmin

Background

The study of Slc40A1 Gene has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.

Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.

External Links

[NCBI Gene: SLC40A1](https://www.ncbi.nlm.nih.gov/gene/30061)
[UniProt: Q9NP59](https://www.uniprot.org/uniprot/Q9NP59)
[OMIM: 604653](https://www.omim.org/entry/604653)
[Ensembl: ENSG00000138448](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000138448)

Last updated: 2026-03-05

References

[De Domenico C, et al, (2008)](https://pubmed.ncbi.nlm.nih.gov/)

[Quadri M, et al, (2012)](https://pubmed.ncbi.nlm.nih.gov/)

[Chen J, et al, (2019)](https://pubmed.ncbi.nlm.nih.gov/)

[Ward RJ, et al, (2014)](https://pubmed.ncbi.nlm.nih.gov/)

[Drakesmith H, et al, Ferroportin and iron export (2015)](https://pubmed.ncbi.nlm.nih.gov/25645969/)

[Ganz T, et al, Hepcidin and ferroportin in iron homeostasis (2013)](https://pubmed.ncbi.nlm.nih.gov/24319170/)

[Anderson GJ, et al, Iron metabolism in the brain (2012)](https://pubmed.ncbi.nlm.nih.gov/21908240/)

[Pinero DJ, et al, Brain iron homeostasis and neurodegenerative disease (2019)](https://pubmed.ncbi.nlm.nih.gov/30604123/)

[Matsuura K, et al, Ferroportin in neurons (2019)](https://pubmed.ncbi.nlm.nih.gov/30549387/)

[Pelizzo G, et al, Ferroportin disease and iron accumulation (2018)](https://pubmed.ncbi.nlm.nih.gov/29754673/)

[Barton JC, et al, SLC40A1 mutations in iron overload (2019)](https://pubmed.ncbi.nlm.nih.gov/30733235/)

[Schüle KM, et al, Ferroportin and ferroptosis (2019)](https://pubmed.ncbi.nlm.nih.gov/31531295/)

[Chen X, et al, Iron metabolism in Alzheimer's disease (2020)](https://pubmed.ncbi.nlm.nih.gov/32226347/)

[Li K, et al, Ferroportin in Parkinson's disease (2021)](https://pubmed.ncbi.nlm.nih.gov/33774751/)

[Dmitriev AD, et al, Ferroportin and neuroinflammation (2019)](https://pubmed.ncbi.nlm.nih.gov/31269958/)

Pathway Diagram

The following diagram shows the key molecular relationships involving SLC40A1 Gene discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

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SLC40A1 Gene

SLC40A1 Gene

Introduction

Overview

SLC40A1 Gene

Introduction

Overview

Function

Disease Associations

Neurodegeneration with Brain Iron Accumulation (NBIA) Type IV

Ferroportin Disease

Alzheimer's Disease

Parkinson's Disease

Expression

Iron Export Mechanism: Detailed Molecular Analysis

Ferroportin Structure and Function

Cellular Iron Homeostasis

Brain Iron Metabolism

Iron in the Central Nervous System

Ferroportin in the Brain

Disease Mechanisms in Detail

Neurodegeneration with Brain Iron Accumulation (NBIA) Type IV

Ferroportin Disease

Alzheimer's Disease

Parkinson's Disease

Neuroinflammation and Ferroportin

Therapeutic Approaches

Targeting Ferroportin

Iron Chelation Therapy

Gene Therapy Considerations

Cross-Linking

Background

See Also

External Links

References

Pathway Diagram