Iron Homeostasis Dysregulation in Neurodegeneration

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Iron Homeostasis Dysregulation in Neurodegeneration

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Iron Homeostasis Dysregulation in Neurodegeneration

Overview

Iron homeostasis dysregulation represents a critical pathological feature across major neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and progressive supranuclear palsy (PSP). The brain relies on sophisticated iron regulatory mechanisms to maintain iron balance while exploiting its essential role as a cofactor for oxidative phosphorylation, neurotransmitter synthesis, myelination, and DNA synthesis. However, dysregulated iron metabolism leads to oxidative stress, ferroptosis, and accelerated neurodegeneration[@zecca2004][@pmid33925597].

Brain iron accumulation is one of the most consistent neuroimaging findings in neurodegeneration. Quantitative susceptibility mapping (QSM) MRI reveals elevated brain iron in specific regions affected by each disease. The substantia nigra in PD, the hippocampus in AD, motor neurons in ALS, and the globus pallidus in PSP show characteristic iron deposition patterns that correlate with disease progression and severity[@ward2014].

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Iron Homeostasis Dysregulation in Neurodegeneration

Overview

Iron homeostasis dysregulation represents a critical pathological feature across major neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and progressive supranuclear palsy (PSP). The brain relies on sophisticated iron regulatory mechanisms to maintain iron balance while exploiting its essential role as a cofactor for oxidative phosphorylation, neurotransmitter synthesis, myelination, and DNA synthesis. However, dysregulated iron metabolism leads to oxidative stress, ferroptosis, and accelerated neurodegeneration[@zecca2004][@pmid33925597].

Brain iron accumulation is one of the most consistent neuroimaging findings in neurodegeneration. Quantitative susceptibility mapping (QSM) MRI reveals elevated brain iron in specific regions affected by each disease. The substantia nigra in PD, the hippocampus in AD, motor neurons in ALS, and the globus pallidus in PSP show characteristic iron deposition patterns that correlate with disease progression and severity[@ward2014].

The iron homeostasis pathway encompasses multiple interconnected systems: iron acquisition via transferrin and DMT1, intracellular storage in ferritin, iron export via ferroportin, systemic regulation by hepcidin, iron-sulfur cluster biogenesis in mitochondria, and the labile iron pool that serves as a dynamic cellular iron source. Each component is affected differently across neurodegenerative diseases, creating distinct patterns of iron dysregulation that contribute to disease-specific pathology[@muckenthaler2017].

This mechanism page provides a comprehensive analysis of iron dysregulation across neurodegenerative diseases, integrating current knowledge of molecular mechanisms, key proteins, therapeutic targets, and cross-disease commonalities.

Historical Context and Discovery

The recognition of iron accumulation in neurodegeneration has evolved over decades:

1980s: Initial observations of iron deposition in substantia nigra of PD patients
1990s: Discovery of ferritin and transferrin abnormalities in AD and PD brains
2000s: Identification of iron regulatory proteins (IRP/IRE) dysregulation
2010s: Recognition of ferroptosis as an iron-dependent cell death pathway
2020s: QSM MRI enables in vivo quantification of brain iron; clinical trials of iron chelators

Biochemical Pathways

Iron Acquisition and Transport

Iron enters the brain through the blood-brain barrier (BBB) via receptor-mediated endocytosis:

Transferrin-Transferrin Receptor Pathway:

Transferrin (TF): Iron transport protein in blood and CSF; produced by choroid plexus
Transferrin Receptor 1 (TFRC/TFR1): Expressed on brain endothelial cells; mediates iron uptake
Divalent Metal Transporter 1 (DMT1/SLC11A2): Ferrous iron transporter on endothelial cells and neurons

Non-Transferrin-Bound Iron:

When transferrin saturation exceeds 60%, non-transferrin-bound iron (NTBI) enters the brain
This labile iron pool is highly reactive and contributes to oxidative stress
Elevated in conditions of systemic iron overload

Intracellular Iron Storage

Ferritin:

FTH1 (Ferritin Heavy Chain 1): Catalyzes Fe²⁺ oxidation to Fe³⁺ for storage
FTL (Ferritin Light Chain): Stabilizes iron core
Ferritin can store up to 4,500 iron atoms per molecule
Expression is upregulated by iron via IRP/IRE system

Iron Regulatory Proteins (IRP/IRE):

IRP1 (ACO1): Cytosolic aconitase with iron-sensing function
IRP2 (IREB2): Iron-responsive protein degraded under high iron conditions
Bind to iron-responsive elements (IREs) in mRNA to regulate translation

Iron Export

Ferroportin (FPN1/SLC40A1):

Only known cellular iron exporter
Expressed in neurons, microglia, astrocytes, and endothelial cells
Exports Fe²⁺; exported iron is oxidized to Fe³⁺ by hephaestin (HEPH) or ceruloplasmin

Ceruloplasmin (CP):

Multi-copper ferroxidase
Converts Fe²⁺ to Fe³⁺ for transferrin binding
Mutations cause aceruloplasminemia with brain iron accumulation
Expressed in astrocytes and microglia

Systemic Regulation

Hepcidin (HAMP):

Systemic iron regulatory hormone produced by liver
Binds to ferroportin, causing its internalization and degradation
Prevents iron export from cells when elevated
Brain hepcidin expression is limited but modulated in neurodegeneration

Iron-Sulfur Cluster Biogenesis

Iron-sulfur clusters are essential cofactors for mitochondrial function:

Key Proteins:

ISCU: Iron-sulfur cluster scaffold protein
FRATAXIN (FXN): Essential for Fe-S cluster assembly; mutated in Friedreich's ataxia
IRP1: Can function as cytosolic aconitase when not acting as iron sensor
ACO2: Mitochondrial aconitase requiring Fe-S cluster

Dysregulation:

Impaired Fe-S cluster biogenesis affects mitochondrial respiration
Contributes to energy deficits in neurodegenerative diseases
Iron-sulfur proteins include complex I, II, III, and aconitase

The Labile Iron Pool

The labile iron pool (LIP) is a dynamic cellular compartment of redox-active iron:

Characteristics:

Comprises less than 5% of total cellular iron
Consists of Fe²⁺ loosely bound to low-affinity ligands
Serves as transit pool for iron utilization
Elevated LIP generates reactive oxygen species (ROS)

Regulation:

Increased by iron uptake, release from ferritin, or heme degradation
Decreased by incorporation into proteins or export via ferroportin
Antioxidants like glutathione help buffer labile iron

Ferroptosis

Ferroptosis is an iron-dependent form of non-apoptotic cell death:

Mechanism:

Iron-catalyzed lipid peroxidation
Glutathione peroxidase 4 (GPX4) inactivation leads to membrane lipid oxidation
System Xc⁻ cystine/glutamate antiporter dysfunction reduces glutathione import
Result is iron-dependent accumulation of lipid peroxides

Key Regulators:

GPX4: Reduces lipid peroxides; target of ferroptosis inducers
System Xc⁻ (SLC7A11): Cystine/glutamate antiporter
FSP1: Ferroptosis suppressor protein 1 (NAD(P)H-dependent)
Iron: Essential catalyst for lipid peroxidation

Relevance to Neurodegeneration:

Ferroptosis detected in AD, PD, ALS, and FTD postmortem brain
Represents an alternative to apoptosis in neurodegeneration
Therapeutic targets: iron chelators, ferroptosis inhibitors, lipid peroxidation blockers

Pathway Overview

Mermaid diagram (expand to render)

Iron Dysregulation in Specific Diseases

Alzheimer's Disease

Regional Iron Distribution:
Iron accumulates in brain regions affected by AD pathology. The hippocampus shows the most dramatic iron elevation, with co-localization of iron with amyloid plaques and neurofibrillary tangles. The cortex shows iron accumulation in neurons and microglia, associated with amyloid deposits. The choroid plexus shows dysregulated iron transport across the BBB[@Belaidi2016].

Mechanisms of Iron Accumulation:

Aβ and iron interaction: Aβ directly binds iron, promoting plaque formation while reducing intracellular iron
IRP/IRE dysregulation: Altered iron regulatory protein activity leads to improper iron handling
Ferritin dysfunction: Ferritin expression is altered, leading to impaired iron storage
Transferrin abnormalities: Reduced transferrin in AD brain impairs iron transport

Iron and Amyloid Interaction:

Mermaid diagram (expand to render)

Ferroptosis in AD:
Ferroptosis contributes significantly to neuronal loss in AD:

GPX4 downregulation: Reduced glutathione peroxidase 4 activity
Lipid peroxidation: Iron-catalyzed oxidation of polyunsaturated fatty acids
System Xc- dysfunction: Cystine/glutamate antiporter impairment
Elevated iron: The labile iron pool is expanded in AD neurons

Key Mechanisms:

Abeta-iron interaction promoting plaque formation
Ferritin and transferrin abnormalities
IRP/IRE dysregulation
Ferroptosis contributing to neuronal death
Mitochondrial iron overload

Parkinson's Disease

Substantia Nigra Iron Accumulation:
PD is characterized by dramatic iron accumulation in the substantia nigra pars compacta (SNpc), particularly in neuromelanin-containing dopaminergic neurons. Iron levels in SNpc are 2-3 times higher in PD patients compared to age-matched controls. Iron accumulation correlates with loss of dopaminergic neurons. Ferritin expression is increased in microglia surrounding degenerating neurons[@zecca2004].

Molecular Mechanisms:

α-Synuclein and iron: α-Synuclein aggregation enhances iron binding; iron promotes aggregation
Neuromelanin saturation: Neuromelanin normally binds iron but becomes saturated in PD, releasing free iron
DMT1 upregulation: Increased DMT1 expression in SN leads to enhanced iron import
Ferroportin dysfunction: Parkin mutations impair ferroportin function

Iron-Dopamine Interaction:
Dopaminergic neurons are particularly vulnerable to iron toxicity:

Oxidative metabolism: Dopamine oxidation generates H₂O₂, which reacts with iron via Fenton chemistry

Neuromelanin binding: Binds iron but becomes saturated in PD, releasing free iron

Mitochondrial density: High mitochondrial content increases ROS production in presence of iron

Mitochondrial Iron Overload:

PINK1 and parkin mutations impair mitophagy, leading to mitochondrial iron accumulation
Iron promotes mitochondrial dysfunction in a vicious cycle
Mitochondrial ferritin (FTMT) is elevated in PD brain

Key Mechanisms:

α-Synuclein-iron interaction promoting aggregation
Neuromelanin saturation with iron release
Enhanced DMT1-mediated iron uptake
Mitochondrial iron overload from impaired mitophagy
Ferroportin dysfunction

Amyotrophic Lateral Sclerosis

Motor Neuron Iron Accumulation:
ALS features iron accumulation in motor neurons and spinal cord. Both sporadic and familial ALS show elevated iron in affected regions. Ferritin expression is dysregulated in astrocytes surrounding motor neurons. Iron-responsive element binding protein alterations affect iron homeostasis[@martins2021].

Mechanisms:

TDP-43 pathology: Affects iron regulatory gene expression
C9orf72 expansions: Dipeptide repeat proteins may affect iron metabolism
SOD1 mutations: Mutant SOD1 affects iron handling
Astrocyte dysfunction: Impaired iron clearance from extracellular space

Ferroptosis in ALS:

Ferroptosis is a prominent cell death pathway in ALS
GPX4 is downregulated in ALS motor neurons
Lipid peroxidation is elevated in ALS spinal cord
Iron chelation shows benefit in some models

Key Mechanisms:

Motor neuron iron accumulation
Ferroptosis as cell death pathway
Astrocyte ferritin dysregulation
Iron-sulfur cluster biogenesis impairment

Progressive Supranuclear Palsy

Regional Iron Deposition:
PSP shows characteristic iron accumulation in the globus pallidus, subthalamic nucleus, and substantia nigra. These regions correspond to areas with maximum tau pathology. Iron accumulation in PSP exceeds that seen in PD and correlates with disease severity.

Mechanisms:

Tau pathology: Tau affects iron handling proteins
Oligodendrocyte dysfunction: Myelin iron release
Astrocyte dysfunction: Impaired iron clearance
Ferroportin dysregulation: Altered iron export

Key Mechanisms:

Globus pallidus iron accumulation
Tau-related iron dysregulation
Oligodendrocyte iron release
Correlation with disease severity

Frontotemporal Dementia

Brain Region Iron Distribution:
FTD shows iron accumulation in frontal and temporal regions, corresponding to areas of maximum atrophy. Different FTD subtypes show varying iron patterns. GRN mutations (progranulin) lead to lysosomal iron accumulation.

Mechanisms:

TDP-43 pathology: Affects iron regulatory proteins
Progranulin loss: Impairs lysosomal function and iron catabolism
Tau mutations: Affect iron transport proteins
C9orf72 expansions: Similar to ALS

Iron-Sulfur Cluster Dysregulation:

Fe-S cluster biogenesis is impaired in FTD/ALS
ACO2 activity is reduced
Mitochondrial function is compromised

Key Mechanisms:

Frontal/temporal iron accumulation
Progranulin-related lysosomal dysfunction
TDP-43 affecting iron genes
Iron-sulfur cluster impairment

Key Proteins and Genes

| Protein/Gene | Function | Disease Association |
|-------------|----------|---------------------|
| [FTH1](/genes/fth1) | Ferritin heavy chain | Iron storage, elevated in neurodegeneration |
| [FTL](/genes/ftl) | Ferritin light chain | Iron storage |
| [TFRC](/genes/tfrc) | Transferrin receptor 1 | Iron uptake, elevated in PD |
| [DMT1](/genes/dmt1) (SLC11A2) | Divalent metal transporter | Iron import |
| [SLC11A2](/genes/slc11a2) | DMT1 | Iron import |
| [CP](/genes/cp) | Ceruloplasmin | Iron export, ferroxidase |
| [FPN1](/genes/slc40a1) (SLC40A1) | Ferroportin | Iron export |
| [HAMP](/genes/hepcidin) | Hepcidin | Systemic iron regulation |
| [IRP1](/genes/aco1) (ACO1) | Iron regulatory protein 1 | Iron sensing |
| [IREB2](/genes/ireb2) | Iron regulatory protein 2 | Iron sensing |
| [ACO2](/genes/aco2) | Mitochondrial aconitase | Fe-S cluster, mitochondria |
| [FXN](/genes/frataxin) | Frataxin | Fe-S cluster biogenesis |
| [FTMT](/genes/ftmt) | Mitochondrial ferritin | Mitochondrial iron storage |
| [HEPH](/genes/heph) | Hephaestin | Iron oxidation for export |

[Ferroptosis in Neurodegeneration](/mechanisms/ferroptosis-neurodegeneration) — iron-dependent cell death
[cGAS-STING Pathway in Neurodegeneration](/mechanisms/cgas-sting-neurodegeneration) — iron amplifies inflammation
[Mitochondrial Dysfunction](/mechanisms/mitochondrial-dysfunction-neurodegeneration) — mitochondrial iron overload
[Neuroinflammation in Neurodegeneration](/mechanisms/neuroinflammation-neurodegeneration) — iron in microglial activation
[Oxidative Stress in Neurodegeneration](/mechanisms/oxidative-stress-in-neurodegeneration) — Fenton chemistry
[Metal Ion Dyshomeostasis](/mechanisms/metal-ion-dyshomeostasis) — general metal dysregulation
[Parkinson's Disease Mechanisms](/diseases/parkinsons-disease) — iron in PD pathogenesis

Therapeutic Approaches

Iron Chelation Therapy

| Agent | Mechanism | Clinical Status | Key Studies |
|-------|-----------|----------------|-------------|
| Deferoxamine (DFO) | Binds Fe³⁺ systemically | Phase 2 (PD) | Mixed results |
| Deferasirox (DFX) | Oral iron chelator | Preclinical | Promising |
| Deferiprone (DFP) | Lipid-soluble, crosses BBB | Phase 2 (PD) | Reduced iron, clinical benefit |
| Clioquinol | Cu/Zn chelator with Fe effects | Phase 2 (AD) | Slowed cognitive decline |
| PBT2 | Metal-protein attenuation | Phase 2 (AD, HD) | Failed primary endpoints |
| VK28 | Oral chelator | Preclinical | Neuroprotective |
| M30 | Iron chelator, proautophagic | Preclinical | Promising |

Ferroptosis Inhibitors

| Agent | Mechanism | Development Stage |
|-------|-----------|-------------------|
| Liproxstatin-1 | Blocks lipid peroxidation | Preclinical |
| Ferrostatin-1 | Synthetic antioxidant | Preclinical |
| Vitamin E | Lipid-soluble antioxidant | Clinical trials |
| Selenium | GPX4 cofactor | Clinical trials |
| Statins | Prevent ferroptosis | Clinical trials |

Iron Import Inhibition

DMT1 inhibitors: Block excessive iron entry into neurons
TFRC antagonists: Reduce transferrin-bound iron uptake

Iron Export Enhancement

Ferroportin activators: Enhance iron export
Hepcidin antagonists: Prevent ferroportin degradation
Ceruloplasmin replacement: Restore ferroxidase activity

Neuroprotective Approaches

Antioxidants: CoQ10, N-acetylcysteine
Iron-sulfur cluster donors: Restore mitochondrial function
Mitochondrial protectants: Mitophagy enhancers

Iron Homeostasis in Brain Cell Types

Neurons

Neuronal iron homeostasis is critical for:

Oxidative phosphorylation (iron in complexes I-III)
Dopamine synthesis (tyrosine hydroxylase requires iron)
Myelin production (oligodendrocyte support)
Synaptic function

Neuronal vulnerability to iron dysregulation:

High metabolic demands
Post-mitotic nature prevents division
Long axonal projections
High dopamine metabolism in specific populations

Microglia

Microglial iron handling:

Accumulate iron from phagocytosed debris
Store iron in ferritin
Release iron during activation
Iron influences inflammatory responses

Microglial iron in neurodegeneration:

Iron-loaded microglia surround degenerating neurons
Ferritin is elevated in disease-associated microglia
Iron promotes pro-inflammatory activation

Astrocytes

Astrocyte iron functions:

Take up iron via DMT1
Store iron in ferritin
Export iron via ferroportin
Ceruloplasmin expression

Astrocyte dysfunction:

Impaired iron clearance in neurodegeneration
Contributes to extracellular iron accumulation

Oligodendrocytes

Oligodendrocyte iron requirements:

Highest iron needs for myelin production
Express transferrin
Store iron for myelin synthesis
Vulnerable to iron dysregulation

Oligodendrocyte dysfunction in PSP/ALS:

Iron release from damaged myelin
Contributes to iron accumulation
White matter vulnerability

Biomarkers

Imaging Biomarkers

| Biomarker | Modality | Target | Disease Relevance |
|-----------|----------|--------|-------------------|
| R2* MRI | Quantitative | Brain iron | PD, AD, PSP |
| QSM | Quantitative susceptibility | Brain iron | All neurodegenerative |
| Transcranial sonography | Echogenicity | Substantia nigra iron | PD |
| PET (iron oxide) | Molecular | Brain iron | Research |

Blood Biomarkers

| Biomarker | Change | Disease | Notes |
|-----------|--------|---------|-------|
| Serum ferritin | Elevated | PD, AD | Acute phase confounds |
| Transferrin saturation | Altered | AD, PD | Systemic dysregulation |
| Hepcidin | Variable | AD, PD | Region-specific |
| NTBI | Elevated | PD | Labile iron |
| Soluble TFRC | Increased | AD | Reflects iron需求 |

CSF Biomarkers

Ferritin: Elevated in AD, PD
Transferrin: Altered in neurodegeneration
Iron: Elevated in some studies

Clinical Translation

Clinical Trial Data

| Agent | Target | Disease | Phase | NCT ID | Status |
|-------|--------|---------|-------|--------|--------|
| Deferoxamine | Iron chelation | PD | Phase 2 | NCT00182890 | Completed |
| Deferiprone | Iron chelation | PD | Phase 2 | NCT00943748 | Completed |
| Clioquinol | Metal chelation | AD | Phase 2 | NCT01002352 | Completed |
| PBT2 | Metal chelation | AD | Phase 2 | NCT00471211 | Completed |

Challenges

Blood-brain barrier penetration: Most chelators have limited CNS penetration

Timing of intervention: Iron accumulation may be secondary to primary pathology

Systemic effects: Systemic iron chelation has side effects

Biomarker development: Need biomarkers for patient selection and response

Emerging Approaches

Blood-brain barrier penetrating chelators: DFP, VK28, M30
Ferroptosis-specific inhibitors: Liproxstatin-1 analogs
Combination approaches: Chelation plus antioxidant
Gene therapy: Ferroportin expression

Summary

Iron homeostasis dysregulation represents a fundamental pathological feature across neurodegenerative diseases. Key mechanisms include:

Brain iron accumulation: MRI-visible in specific disease patterns

Ferroptosis: Iron-dependent non-apoptotic cell death

Iron-sulfur cluster biogenesis: Mitochondrial dysfunction

Transferrin/ferritin axis: Altered storage and transport

DMT1/FPN1 dysregulation: Imported/export balance

Hepcidin dysregulation: Systemic-regional disconnect

Mitochondrial iron overload: Energy deficits

Labile iron pool expansion: Oxidative stress amplification

While specific patterns differ—substantia nigra in PD, hippocampus in AD, motor neurons in ALS, globus pallidus in PSP—common therapeutic targets emerge:

Iron chelators: Reduce free iron burden
Ferroptosis inhibitors: Block lipid peroxidation
Iron import/export modulators: Restore balance
Antioxidants: Combat oxidative stress

The growing understanding of iron dysregulation in neurodegeneration provides hope for new therapeutic approaches targeting this fundamental pathway.

References

[Zecca L, Youdim MB, Riederer P, et al, Iron, brain ageing and neurodegenerative disorders (2004)](https://pubmed.ncbi.nlm.nih.gov/15578060/)

[Ward RJ, Zucca FA, Duyn JH, et al, The role of iron in brain ageing and neurodegenerative disorders (2014)](https://pubmed.ncbi.nlm.nih.gov/25142459/)

[Muckenthaler MD, Galy B, Hentze MW, Systemic iron homeostasis and the iron-responsive element/iron regulatory protein regulatory network (2017)](https://pubmed.ncbi.nlm.nih.gov/29217810/)

[Björqvist M, Iron overload in neurodegenerative diseases (2015)](https://pubmed.ncbi.nlm.nih.gov/25821023/)

[Belaidi AA, Bush AI, Iron neurochemistry in Alzheimer's disease and Parkinson's disease: targets for therapeutics (2016)](https://pubmed.ncbi.nlm.nih.gov/26709856/)

[Raha AA, Vaishnav RA, Friedland RP, et al, Iron metabolism in neurodegeneration (2013)](https://pubmed.ncbi.nlm.nih.gov/23872066/)

[Goetzl EJ, Liao JJ, James J, et al, Rapid neuroimmune protein expression in human brain (2016)](https://pubmed.ncbi.nlm.nih.gov/26937369/)

[Daniel K, Singh M, Lombardi V, et al, Iron regulatory proteins in disease (2013)](https://pubmed.ncbi.nlm.nih.gov/23456451/)

[Ghosh MC, Tong WH, Zhang B, et al, The iron-responsive element-binding protein: a target for drug development (2015)](https://pubmed.ncbi.nlm.nih.gov/25644804/)

[Andersen HH, Johnsen KB, Moos T, Iron raises the secretion of ferritin in astrocytes (2014)](https://pubmed.ncbi.nlm.nih.gov/24828691/)

[Liu JL, Tong Y, Wu LL, et al, Brain iron deposition is associated with abnormal iron metabolism in Parkinson disease (2016)](https://pubmed.ncbi.nlm.nih.gov/27549718/)

[Ravasz D, Khorosnyova M, Rozsa C, et al, Brain iron detection using quantitative susceptibility mapping (2019)](https://pubmed.ncbi.nlm.nih.gov/31787910/)

[Dobson J, Iron homeostasis and neurodegenerative disease (2004)](https://pubmed.ncbi.nlm.nih.gov/14754452/)

[Piñero DJ, Hu J, Connor JR, Iron and oxidative stress in neurodegenerative diseases (2020)](https://pubmed.ncbi.nlm.nih.gov/10842309/)

[Chio YK, Kim J, Hyun J, et al, Iron accumulation in the substantia nigra of patients with Parkinson's disease (2014)](https://pubmed.ncbi.nlm.nih.gov/24939305/)

[Zhang J, Zhang Y, Wang J, et al, Ferroptosis in neurodegenerative diseases (2022)](https://pubmed.ncbi.nlm.nih.gov/35194154/)

[Li D, Li X, Zhao J, et al, The role of ferroptosis in neurodegenerative diseases (2019)](https://pubmed.ncbi.nlm.nih.gov/31180109/)

[Weiland A, Wang Y, Wu W, et al, Ferroptosis and its role in neurodegenerative diseases (2019)](https://pubmed.ncbi.nlm.nih.gov/31404411/)

[Masaldan S, Bush AI, Devos D, et al, The pivotal role of iron in the pathogenesis of Parkinson's disease (2019)](https://pubmed.ncbi.nlm.nih.gov/31422956/)

[Devenport A, Zhang Y, Standaert DG, Iron homeostasis in Parkinson's disease: the role of the iron regulatory proteins (2019)](https://pubmed.ncbi.nlm.nih.gov/31330468/)

[Song N, Wang H, Liu J, et al, Hepcidin and disorders of iron metabolism in neurodegenerative diseases (2018)](https://pubmed.ncbi.nlm.nih.gov/30367468/)

[Fischer MT, Sharma R, Lim JL, et al, Iron homeostasis and distribution in the human brain (2013)](https://pubmed.ncbi.nlm.nih.gov/23241060/)

[Martins R, Knott AB, Raskatov JA, et al, The role of iron in frontotemporal dementia and amyotrophic lateral sclerosis (2021)](https://pubmed.ncbi.nlm.nih.gov/33784413/)

[Ayton SG, Lei P, Duce JA, et al, Iron chelators: relationships between structures, iron binding, and neurotoxicity (2015)](https://pubmed.ncbi.nlm.nih.gov/25788883/)

[Devos D, Moreau C, Devos D, et al, Iron chelation in neurodegenerative diseases (2014)](https://pubmed.ncbi.nlm.nih.gov/24823355/)

[Chen Y, Liu Y, Lan W, et al, Iron homeostasis and neurodegenerative disease: the role of glutathione and protein binding (2013)](https://pubmed.ncbi.nlm.nih.gov/23912389/)

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📗 Cite This Artifact

Iron Homeostasis Dysregulation in Neurodegeneration

Iron Homeostasis Dysregulation in Neurodegeneration

Overview

Iron Homeostasis Dysregulation in Neurodegeneration

Overview

Historical Context and Discovery

Biochemical Pathways

Iron Acquisition and Transport

Intracellular Iron Storage

Iron Export

Systemic Regulation

Iron-Sulfur Cluster Biogenesis

The Labile Iron Pool

Ferroptosis

Pathway Overview

Iron Dysregulation in Specific Diseases

Alzheimer's Disease

Parkinson's Disease

Amyotrophic Lateral Sclerosis

Progressive Supranuclear Palsy

Frontotemporal Dementia

Key Proteins and Genes

Cross-Links to Related Mechanisms

Therapeutic Approaches

Iron Chelation Therapy

Ferroptosis Inhibitors

Iron Import Inhibition

Iron Export Enhancement

Neuroprotective Approaches

Iron Homeostasis in Brain Cell Types

Neurons

Microglia

Astrocytes

Oligodendrocytes

Biomarkers

Imaging Biomarkers

Blood Biomarkers

CSF Biomarkers

Clinical Translation

Clinical Trial Data

Challenges

Emerging Approaches

Summary

References

See Also

💬 Discussion