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SLC40A1 Gene
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]
<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 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]:
- 12 transmembrane domains
- Multiple iron-binding sites
- Basolateral (systemic) localization in polarized cells
- 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
- 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]:
- Transferrin receptor-mediated endocytosis
- DMT1 (divalent metal transporter 1) for Fe²⁺ entry
- Limited ferroportin expression at BBB
- Transferrin-bound iron uptake via TfR1/TfR2
- DMT1 for intracellular iron release
- Limited export capacity in neurons
- 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
- 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
| 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
- Hepcidin-resistant ferroportin
- Elevated transferrin saturation
- Classic hemochromatosis phenotype
Alzheimer's Disease
Ferroportin dysfunction contributes to AD pathogenesis [@chen2020]:
- Iron accumulation in AD brain regions (frontal cortex, hippocampus)
- Elevated ferritin in cerebrospinal fluid
- Altered iron regulatory proteins
- Iron-dependent cell death pathway
- Lipid peroxidation in neurons
- GPX4 downregulation in AD brain
- Iron catalyzes Aβ aggregation
- Aβ co-localizes with iron in plaques
- Iron promotes oxidative stress
- Iron chelation approaches under investigation
- Ferroportin modulators as potential treatment
- Antioxidant strategies targeting iron
Parkinson's Disease
Iron metabolism alterations in PD [@li2021]:
- Markedly elevated iron in PD substantia nigra
- Especially in dopaminergic neurons
- Correlation with disease severity
- Reduced ferroportin in PD brain
- Altered hepcidin/ferroportin axis
- Dysregulated iron export
- Iron promotes dopaminergic neuron loss
- Oxidative stress contribution
- Mitochondrial dysfunction
- Iron chelation (deferoxamine, deferasirox)
- Ferroportin activators
- Antioxidant approaches
Neuroinflammation and Ferroportin
Ferroportin plays a role in neuroimmune interactions [@dmitriev2019]:
- Activated microglia accumulate iron
- Ferroportin upregulation in inflammation
- Altered iron release affects neurons
- IL-6 modulates ferroportin expression
- LPS reduces ferroportin in macrophages
- TNF-α affects neuronal iron homeostasis
- 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.
See Also
- [Alzheimer's Disease](/diseases/alzheimers-disease)
- [Parkinson's Disease](/diseases/parkinsons-disease)
- Neurodegeneration with Brain Iron Accumulation (NBIA)
- [Iron Metabolism](/mechanisms/iron-metabolism-neurodegeneration) Ferroptosis
- TF Gene
- FTH1 Gene
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)
References
Pathway Diagram
The following diagram shows the key molecular relationships involving SLC40A1 Gene discovered through SciDEX knowledge graph analysis:
▸Metadataorigin_type: v1_polymorphic_backfill
| slug | genes-slc40a1 |
| kg_node_id | SLC40A1 |
| entity_type | gene |
| origin_type | v1_polymorphic_backfill |
| source_table | wiki_pages |
| wiki_page_id | wp-3bf0a2cca82f |
| __merged_from | {'merged_at': '2026-05-13', 'unprefixed_id': 'genes-slc40a1'} |
| _schema_version | 1 |
No provenance edges found
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