NCOA4 Gene

NCOA4 Gene

Pathway Diagram

```mermaid
flowchart TD
NCOA4["NCOA4<br/>Nuclear Receptor<br/>Coactivator 4"]

Ferritinophagy["Ferritinophagy<br/>Iron Release from<br/>Ferritin"]

Iron_Pool["Cellular Iron<br/>Pool"]

GPX4["GPX4<br/>Glutathione<br/>Peroxidase 4"]

Ferroptosis["Ferroptosis<br/>Iron-dependent<br/>Cell Death"]

SLC7A11["SLC7A11<br/>Cystine/Glutamate<br/>Antiporter"]

Autophagy["Autophagy<br/>Pathway"]

ALS["Amyotrophic<br/>Lateral Sclerosis"]

MS["Multiple<br/>Sclerosis"]

Parkinsons["Parkinson's<br/>Disease"]

Neurodegeneration["Neuronal<br/>Death"]

Oxidative_Stress["Oxidative<br/>Stress"]

Iron_Homeostasis["Iron<br/>Homeostasis<br/>Disruption"]

Therapeutic_Target["Therapeutic<br/>Intervention<br/>Target"]

NCOA4 -->|"mediates"| Ferritinophagy
Ferritinophagy -->|"releases"| Iron_Pool
Iron_Pool -->|"promotes"| Oxidative_Stress
NCOA4 -->|"inhibits"| GPX4
GPX4 -->|"protects_against"| Ferroptosis
NCOA4 -->|"regulates"| Ferroptosis
Iron_Pool -->|"drives"| Ferroptosis
SLC7A11 -->|"inhibits"| Ferroptosis
NCOA4 -->|"regulates"| Autophagy
Ferroptosis -->|"causes"| Neurodegeneration
Oxidative_Stress -->|"leads_to"| Neurodegeneration
NCOA4 -->|"activates"| ALS
NCOA4 -->|"regulates"| MS
NCOA4 -->|"associated_with"| Parkinsons
ALS -->|"involves"| Neurodegeneration
MS -->|"involves"| Neurodegeneration
Parkinsons -->|"involves"| Neurodegeneration
Iron_Pool -->|"disrupts"| Iron_Homeostasis

NCOA4 Gene

Pathway Diagram

title: NCOA4 Gene

NCOA4 (Nuclear Receptor Coactivator 4)

Overview

NCOA4 is a multifunctional protein that serves as a selective cargo receptor for ferritinophagy, the autophagic degradation of ferritin. This process releases iron for cellular use and is critical in neurodegenerative diseases involving iron dysregulation. [@kohan2015]

Introduction

NCOA4 (Nuclear Receptor Coactivator 4) was originally identified as a transcriptional coactivator for nuclear receptors, but has gained importance in neurodegeneration research as the key receptor mediating ferritinophagy. Iron accumulation in the brain is a hallmark of several neurodegenerative diseases, and NCOA4-mediated ferritinophagy plays a central role in iron homeostasis. [@bogdan2016]

<div class="infobox infobox-gene">

| Property | Value |
|----------|-------|
| Gene Symbol | NCOA4 |
| Full Name | Nuclear Receptor Coactivator 4 |
| Chromosomal Location | 10q11.23 |
| NCBI Gene ID | 8031 |
| OMIM ID | 605161 |
| Ensembl ID | ENSG00000135333 |
| UniProt ID | Q9UBR1 |
| Encoded Protein | NCOA4 protein |
| Associated Diseases | Alzheimer's disease, Parkinson's disease, neurodegeneration with brain iron accumulation |

</div>

Function

NCOA4 performs two major functions in the cell:

Transcriptional Coactivator Function

• Binds to nuclear receptors including thyroid hormone receptors, retinoic acid receptors, and estrogen receptors
• Enhances transcriptional activation by recruiting coactivators like CBP/p300
• Regulates genes involved in metabolism, reproduction, and development

Ferritinophagy Receptor Function (Primary in Neurodegeneration)

• Acts as a selective cargo receptor for [autophagy](/entities/autophagy)
• Binds to ferritin (FTH1/FTL) and delivers it to autophagosomes
• Critical for releasing stored iron during iron deficiency
• Regulates cellular iron homeostasis through autophagic degradation

• Maintaining iron homeostasis in [neurons](/entities/neurons)
• Preventing iron accumulation that leads to oxidative stress
• Supporting mitochondrial function
• Regulating [ferroptosis](/entities/ferroptosis) sensitivity

Disease Associations

Alzheimer's Disease

• NCOA4-mediated ferritinophagy is impaired in AD brains
• Iron accumulation in amyloid plaques and neurons
• Dysregulation contributes to oxidative stress and neurodegeneration
• Therapeutic targeting of ferritinophagy is being explored

Parkinson's Disease

• Iron accumulation in substantia nigra dopaminergic neurons
• NCOA4 expression is altered in PD models
• Ferritinophagy deficits lead to increased oxidative stress
• Iron chelation therapies may work partly through ferritinophagy modulation

Neurodegeneration with Brain Iron Accumulation (NBIA)

• Genetic variants in NCOA4 are associated with certain NBIA subtypes
• Impaired ferritinophagy leads to iron overload
• Animal models show movement disorders similar to human NBIA

Expression

NCOA4 is widely expressed in human tissues:

• Brain: Moderate expression in [cortex](/brain-regions/cortex), [hippocampus](/brain-regions/hippocampus), basal ganglia
• Highest expression: Liver, pancreas, small intestine
• Cellular localization: Cytoplasmic, with nuclear shuttling

• Neurons (especially pyramidal neurons in cortex)
• [Astrocytes](/entities/astrocytes)
• [Microglia](/cell-types/microglia-neuroinflammation)
• [Oligodendrocytes](/cell-types/oligodendrocytes)

Key Publications

Cross-Links

• [Ferritin](/proteins/ferritin) - The primary cargo of NCOA4-mediated autophagy
• [Iron homeostasis](/mechanisms/iron-homeostasis) - Pathway involving NCOA4
• [Ferroptosis](/mechanisms/ferroptosis) - Iron-dependent cell death pathway
• [Autophagy](/mechanisms/autophagy) - NCOA4 functions in selective autophagy
• [Alzheimer's disease](/diseases/alzheimers-disease) - Disease association
• [Parkinson's disease](/diseases/parkinsons-disease) - Disease association
• [FTH1](/genes/fth1) - Ferritin heavy chain
• [FTL](/genes/ftl) - Ferritin light chain

See Also

• [Neurodegeneration](/diseases/neurodegeneration) — General mechanisms

External Links

• [GeneCards](https://www.genecards.org/)
• [NCBI Gene](https://www.ncbi.nlm.nih.gov/gene/)

References

Pathway Diagram

The following diagram shows the key molecular relationships involving NCOA4 Gene discovered through SciDEX knowledge graph analysis: