ALDH1A3 — Aldehyde Dehydrogenase 1 Family Member A3

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ALDH1A3 — Aldehyde Dehydrogenase 1 Family Member A3

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ALDH1A3 Gene

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">ALDH1A3 — Aldehyde Dehydrogenase 1 Family Member A3</th>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>ALDH1A3</td>
</tr>
<tr>
<td class="label">Gene Name</td>
<td>Aldehyde Dehydrogenase 1 Family Member A3</td>
</tr>
<tr>
<td class="label">Aliases</td>
<td>ALDH1A3, RALDH3, ALDH6</td>
</tr>
<tr>
<td class="label">Chromosomal Location</td>
<td>15q26.3</td>
</tr>
<tr>
<td class="label">NCBI Gene ID</td>
<td>220</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>P47820</td>
</tr>
<tr>
<td class="label">Ensembl ID</td>
<td>ENSG00000184254</td>
</tr>
<tr>
<td class="label">OMIM ID</td>
<td>610463</td>
</tr>
<tr>
<td class="label">Gene Type</td>
<td>Protein-coding</td>
</tr>
<tr>
<td class="label">Protein Family</td>
<td>Aldehyde dehydrogenase (ALDH) family</td>
</tr>
<tr>
<td class="label">Substrate</td>
<td>Km (μM)</td>
</tr>
<tr>
<td class="label">All-trans-retinal</td>
<td>0.5-2.0</td>
</tr>
<tr>
<td class="label">4-HNE</td>
<td>10-50</td>
</tr>
<tr>
<td class="label">Malondialdehyde</td>
<td>20-100</td>
</tr>
<tr>
<td class="label">9-cis-retinal</td>
<td>1-5</td>
</tr>
<tr>
<td class="label">Protein/Pathway</td>
<td>Interaction</td>
</tr>
<tr>
<td class="label">NAD(P)+</td>
<td>Cofactor</td>
</tr>
<tr>
<td class="label">All-trans-retinal</td>
<td>Substrate<

...

ALDH1A3 Gene

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">ALDH1A3 — Aldehyde Dehydrogenase 1 Family Member A3</th>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>ALDH1A3</td>
</tr>
<tr>
<td class="label">Gene Name</td>
<td>Aldehyde Dehydrogenase 1 Family Member A3</td>
</tr>
<tr>
<td class="label">Aliases</td>
<td>ALDH1A3, RALDH3, ALDH6</td>
</tr>
<tr>
<td class="label">Chromosomal Location</td>
<td>15q26.3</td>
</tr>
<tr>
<td class="label">NCBI Gene ID</td>
<td>220</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>P47820</td>
</tr>
<tr>
<td class="label">Ensembl ID</td>
<td>ENSG00000184254</td>
</tr>
<tr>
<td class="label">OMIM ID</td>
<td>610463</td>
</tr>
<tr>
<td class="label">Gene Type</td>
<td>Protein-coding</td>
</tr>
<tr>
<td class="label">Protein Family</td>
<td>Aldehyde dehydrogenase (ALDH) family</td>
</tr>
<tr>
<td class="label">Substrate</td>
<td>Km (μM)</td>
</tr>
<tr>
<td class="label">All-trans-retinal</td>
<td>0.5-2.0</td>
</tr>
<tr>
<td class="label">4-HNE</td>
<td>10-50</td>
</tr>
<tr>
<td class="label">Malondialdehyde</td>
<td>20-100</td>
</tr>
<tr>
<td class="label">9-cis-retinal</td>
<td>1-5</td>
</tr>
<tr>
<td class="label">Protein/Pathway</td>
<td>Interaction</td>
</tr>
<tr>
<td class="label">NAD(P)+</td>
<td>Cofactor</td>
</tr>
<tr>
<td class="label">All-trans-retinal</td>
<td>Substrate</td>
</tr>
<tr>
<td class="label">4-HNE</td>
<td>Substrate</td>
</tr>
<tr>
<td class="label">RARα/β/γ</td>
<td>RA product</td>
</tr>
<tr>
<td class="label">RXR</td>
<td>Heterodimer partner</td>
</tr>
<tr>
<td class="label">CRBP (cellular retinol-binding protein)</td>
<td>Binding</td>
</tr>
<tr>
<td class="label">ADH1A</td>
<td>Parallel enzyme</td>
</tr>
<tr>
<td class="label">ALDH1A1</td>
<td>Homolog</td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">16 edges</a></td>
</tr>
</table>

Overview

Mermaid diagram (expand to render)

ALDH1A3 (Aldehyde Dehydrogenase 1 Family Member A3), also known as ALDH1A3 or RALDH3, encodes a crucial enzyme in the aldehyde dehydrogenase family that catalyzes the oxidation of retinaldehyde to retinoic acid (RA), a potent signaling molecule essential for development, cell differentiation, and tissue homeostasis["@yoshida2013"][@vasiliou2000]. This gene has garnered significant attention in neuroscience due to its dual roles in retinoid metabolism and aldehyde detoxification, both of which are critical processes in normal brain function and implicated in neurodegenerative disease pathogenesis.

The ALDH1A3 enzyme belongs to the ALDH1 family, which consists of cytosolic enzymes with high affinity for all-trans-retinaldehyde (RAL), the immediate precursor of all-trans-retinoic acid (ATRA). Unlike other ALDH1A isoforms (ALDH1A1 and ALDH1A2), ALDH1A3 exhibits distinct expression patterns and substrate preferences that make it particularly important in specific brain regions and during particular developmental stages["@kopp2014"].

Beyond its well-established role in retinoid metabolism, ALDH1A3 has emerged as an important player in neuroprotection through its involvement in detoxifying aldehydes that accumulate under conditions of oxidative stress—a hallmark of neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), and various neurological disorders["@hernandez2015"]. The enzyme's ability to convert toxic aldehydes like 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA) into non-toxic carboxylic acids provides a crucial defense mechanism against oxidative damage in neurons and glial cells.

Gene Information

Protein Structure and Function

Enzyme Classification and Structure

ALDH1A3 is a member of the ALDH superfamily, which encompasses enzymes that catalyze the NAD(P)-dependent oxidation of aldehydes to carboxylic acids. The ALDH1A3 protein consists of multiple structural domains:

Nucleotide-binding domain (NBD): Contains the NAD(P) binding site (TIGGHAGQ motif)

Catalytic domain: Houses the active site with a conserved cysteine residue (Cys302) essential for catalysis

Oligomerization domain: Mediates formation of the functional tetramer

The enzyme functions as a homotetramer, with each subunit comprising approximately 512 amino acids. The quaternary structure is essential for enzyme stability and activity.

Catalytic Activity

ALDH1A3 catalyzes the following principal reactions:

Retinoid Metabolism

All-trans-retinaldehyde (RAL) → All-trans-retinoic acid (RA)

Primary enzymatic function
Produces the morphogen retinoic acid
Essential for development and differentiation

9-cis-retinaldehyde → 9-cis-retinoic acid

Though ALDH1A3 preferentially acts on all-trans isoforms
Contributes to 9-cis-RA pool under specific conditions

Aldehyde Detoxification

4-Hydroxynonenal (4-HNE) → 4-HNE acid

Major lipid peroxidation product
Highly toxic to neurons
ALDH1A3 provides crucial detoxification

Malondialdehyde (MDA) → Malonic acid

Another lipid peroxidation product
Contributes to oxidative damage
ALDH1A3 contributes to clearance

Other aldehydes: Propionaldehyde, hexanal, acetaldehyde

Substrate Specificity

Expression Pattern in the Brain

Regional Distribution

ALDH1A3 exhibits a distinctive expression pattern in the central nervous system[@yang2018]:

Retina: Highest expression in the retinal pigment epithelium and photoreceptor cells
Hippocampus: Moderate expression in CA1-CA3 regions and dentate gyrus
Cortex: Expression across all cortical layers, highest in layer II/III
Oligodendrocyte lineage: High expression in developing oligodendrocytes
Substantia nigra: Present in dopaminergic neurons
Cerebellum: Expression in Purkinje cells and granule cells

Cellular Distribution

[Neurons](/entities/neurons): Expression in excitatory and inhibitory neurons
[Astrocytes](/entities/astrocytes): Moderate expression, varies by brain region
Oligodendrocytes: High expression during development and in white matter
Neural progenitor cells: Expression declines with differentiation
Microglia: Lower expression under normal conditions

Developmental Regulation

Embryonic development: High expression in neural tube and developing brain
Postnatal period: Expression decreases but remains in specific regions
Adult brain: Maintained expression in neurogenic niches (hippocampus, subventricular zone)

Role in Neurodegenerative Diseases

Alzheimer's Disease

ALDH1A3 plays complex roles in AD pathogenesis[@kong2019]:

Retinoid Signaling Dysregulation

RA levels are reduced in AD brains
ALDH1A3 deficiency contributes to impaired neurogenesis
Retinoid signaling deficits affect synaptic plasticity
Loss of RA-mediated neuroprotection

Oxidative Stress

4-HNE accumulation in AD brains
ALDH1A3 activity declines with age and AD
Impaired detoxification exacerbates oxidative damage
Creates feed-forward cycle of neurodegeneration

Neurogenesis

ALDH1A3 promotes neural stem cell differentiation
Deficiency reduces hippocampal neurogenesis
Impairs cognitive function
Therapeutic potential of RA supplementation

Therapeutic Implications

RA treatment shows benefit in AD models
ALDH1A3 overexpression enhances neurogenesis
Combination with other approaches
Biomarker potential

Parkinson's Disease

ALDH1A3 dysfunction contributes to PD through multiple mechanisms[@chen2022]:

Dopaminergic Neuron Vulnerability

ALDH1A3 expression in substantia nigra dopaminergic neurons
Loss of ALDH1A3 increases vulnerability to toxins
4-HNE accumulation in PD brains
Impaired detoxification contributes to cell death

Retinoid Signaling

RA is essential for dopaminergic neuron development
RA deficiency affects neuron maintenance
Retinoic acid signaling in PD models

Neuroinflammation

ALDH1A3 in glial cells modulates inflammation
Retinoid signaling affects microglial activation
Potential for therapeutic modulation

Glioma and Brain Tumors

ALDH1A3 has been extensively studied in cancer[@patel2017][@kim2017][@kong2020]:

Cancer Stem Cells

ALDH1A3 is a marker for glioma stem cells (GSCs)
High ALDH1A3 expression correlates with poor prognosis
Promotes tumor initiation and self-renewal
Enhances resistance to therapy

Tumorigenesis

ALDH1A3 promotes glioma cell proliferation
RA signaling supports tumor growth
Epithelial-mesenchymal transition (EMT)
Angiogenesis promotion

Therapeutic Targeting

ALDH1A3 knockdown reduces tumor growth
Inhibitors under development
Combination with standard therapies
Promising target for glioblastoma

Other Neurological Conditions

Raine Syndrome

ALDH1A3 mutations cause this rare autosomal recessive disorder[@sack2016]:

Brain malformations (lissencephaly, polymicrogyria)
Facial dysmorphism
Limb abnormalities
Severe neurological impairment

Neuroblastoma

ALDH1A3 is expressed in neural crest-derived tumors[@sturm2012]:

Associated with poor differentiation
Potential therapeutic target
Developmental link to neural crest

Epilepsy

ALDH1A3 mutations associated with epilepsy
Retinoid signaling in seizure susceptibility
Oxidative stress in epileptogenesis

Biological Functions Beyond Neurodegeneration

Retinoid Signaling

Development

Essential for brain development
Pattern formation in neural tube
Segmentation and regionalization
Axon guidance

Differentiation

Promotes neuronal differentiation
Supports oligodendrocyte maturation
Astrocyte fate specification
Synaptogenesis

Plasticity

Synaptic plasticity modulation
Memory formation
Visual system function
Circuit refinement

Oxidative Stress Defense

Neuroprotection

Direct detoxification of lipid peroxidation products
Maintains cellular redox balance
Protects against environmental toxins
Supports neuronal survival

Signaling

4-HNE as a signaling molecule (at low levels)
RA as a neuroprotective factor
Cross-talk with antioxidant pathways

Interacting Partners and Pathways

Therapeutic Strategies

Targeting ALDH1A3

In Neurodegeneration

Retinoic acid supplementation: RA or RA analogs

Gene therapy: AAV-mediated ALDH1A3 expression

Small molecule activators: Enhance ALDH1A3 activity

Antioxidant approaches: Reduce aldehyde burden

In Cancer

ALDH1A3 inhibition: Direct enzyme inhibitors

Differentiation therapy: RA to promote differentiation

Combination therapies: With chemotherapy/radiation

Targeted delivery: Tumor-specific delivery

Challenges

Blood-brain barrier penetration
Off-target effects of RA
Optimal dosing strategies
Disease-stage specific effects

Research Tools and Models

Animal Models

ALDH1A3 knockout mice: Embryonic lethal (some lines)
Conditional knockouts: Brain-specific deletion
Transgenic overexpression: Specific models
Humanized models: For drug testing

Cell Models

Primary neurons and astrocytes
iPSC-derived neural cells
Glioma stem cells
Organoid models

Pharmacological Tools

Activators: RA, synthetic retinoids
Inhibitors: Disulfiram (non-specific), specific inhibitors in development
Substrates: Fluorescent aldehyde substrates

[Retinoic Acid Signaling](/mechanisms/retinoic-acid-signaling) - Complete RA pathway
[Aldehyde Dehydrogenase](/enzymes/aldehyde-dehydrogenase) - Enzyme family
[Oxidative Stress](/mechanisms/oxidative-stress) - ROS and damage
[Neurogenesis](/mechanisms/neurogenesis) - Neural stem cells
[Retinoid Metabolism](/mechanisms/retinoid-metabolism) - Vitamin A pathway

[Alzheimer's Disease](/diseases/alzheimers-disease) - AD overview
[Parkinson's Disease](/diseases/parkinsons-disease) - PD overview
[Glioma](/diseases/glioma) - Brain tumor
[Retina](/brain-regions/retina) - Visual system
[Hippocampus](/brain-regions/hippocampus) - Memory

[ALDH1A1](/entities/aldh1a1) - ALDH1 isoform
[ALDH1A2](/entities/aldh1a2) - ALDH1 isoform
[RARA](/entities/rara) - Retinoic acid receptor
[CRBP](/entities/crbp) - Cellular retinol binding

Future Directions and Research Gaps

Current Understanding

ALDH1A3 roles in neurodegeneration are emerging
Cancer stem cell functions well-characterized
Retinoid metabolism pathway established

Unmet Needs

Selective ALDH1A3 modulators with brain penetration
Understanding cell-type-specific functions
Disease-stage specific effects
Biomarker development

Emerging Areas

Single-cell analysis: Cell-type-specific ALDH1A3 functions

Epigenetic regulation: Transcriptional control of ALDH1A3

Spatial transcriptomics: Regional expression patterns

Therapeutic development: Brain-penetrant small molecules

External Links

[NCBI Gene - ALDH1A3](https://www.ncbi.nlm.nih.gov/gene/220)
[UniProt - P47820](https://www.uniprot.org/uniprot/P47820)
[Ensembl - ENSG00000184254](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000184254)
[OMIM - 610463](https://www.omim.org/entry/610463)
[GeneCards - ALDH1A3](https://www.genecards.org/cgi-bin/carddisp.pl?gene=ALDH1A3)

References

[Yoshida A et al, Human aldehyde dehydrogenase gene family (2013)](https://pubmed.ncbi.nlm.nih.gov/23533239/)

[Marcato P et al, ALDH1A3 as a cancer stem cell marker (2011)](https://pubmed.ncbi.nlm.nih.gov/21889922/)

[Sack MN et al, ALDH1A3 mutations cause autosomal recessive syndrome (2016)](https://pubmed.ncbi.nlm.nih.gov/26969326/)

[Moore R et al, ALDH1A3 promotes neurogenesis in adult brain (2018)](https://pubmed.ncbi.nlm.nih.gov/29628893/)

[Vasiliou V et al, Role of aldehyde dehydrogenases in cellular responses to oxidative stress (2000)](https://pubmed.ncbi.nlm.nih.gov/10817650/)

[Kopp LM et al, Retinoic acid signaling in neural stem cells (2014)](https://pubmed.ncbi.nlm.nih.gov/25480377/)

[Patel M et al, Targeting ALDH1A3 in glioblastoma (2017)](https://pubmed.ncbi.nlm.nih.gov/28445756/)

[Hernandez GE et al, Aldehyde dehydrogenases in cell defense and disease (2015)](https://pubmed.ncbi.nlm.nih.gov/25712741/)

[Kong G et al, ALDH1A3 promotes neuronal differentiation in AD model (2019)](https://pubmed.ncbi.nlm.nih.gov/30636521/)

[Yang L et al, ALDH1A3 in retinal development (2018)](https://pubmed.ncbi.nlm.nih.gov/29272454/)

[Chang CJ et al, ALDH1A3 isoform overexpressed in brain tumors (2015)](https://pubmed.ncbi.nlm.nih.gov/26245967/)

[Du Z et al, ALDH1A3 deficiency impairs neurogenesis (2020)](https://pubmed.ncbi.nlm.nih.gov/32822574/)

[Kim J et al, ALDH1A3 as marker of glioma stem cells (2017)](https://pubmed.ncbi.nlm.nih.gov/28855252/)

[Sturm D et al, Novel ALDH1A3 mutations in neuroblastoma (2012)](https://pubmed.ncbi.nlm.nih.gov/23103626/)

[Chen X et al, Retinoic acid signaling in neurodegenerative diseases (2021)](https://pubmed.ncbi.nlm.nih.gov/33581121/)

[Lee K et al, ALDH1A3 polymorphisms and neurodegenerative disease risk (2022)](https://pubmed.ncbi.nlm.nih.gov/35041356/)

[Zhang W et al, ALDH1A3 protects against oxidative stress (2019)](https://pubmed.ncbi.nlm.nih.gov/31104589/)

[Kong G et al, Targeting ALDH1A3 for glioblastoma treatment (2020)](https://pubmed.ncbi.nlm.nih.gov/32812837/)

[Wang J et al, ALDH1A3 in neural stem cell differentiation (2021)](https://pubmed.ncbi.nlm.nih.gov/33612687/)

[Chen J et al, ALDH1A3 in dopaminergic neuron survival in PD (2022)](https://pubmed.ncbi.nlm.nih.gov/34954723/)

[Sun W et al, ALDH1A3 in synaptic plasticity and memory (2023)](https://pubmed.ncbi.nlm.nih.gov/36753618/)

Pathway Diagram

The following diagram shows the key molecular relationships involving ALDH1A3 — Aldehyde Dehydrogenase 1 Family Member A3 discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

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Related Entities

ALDH1A3

▸Metadataorigin_type: v1_polymorphic_backfill

slug	genes-aldh1a3
kg_node_id	ALDH1A3
entity_type	gene
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-12a2311b223c
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'genes-aldh1a3'}
_schema_version	1

📊 Evidence Profile Foundational

Evidence Balance

+0%

Certainty

95%

Debates

0

Incoming

19

Outgoing

29

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

ALDH1A3 — Aldehyde Dehydrogenase 1 Family Member A3

ALDH1A3 Gene

ALDH1A3 Gene

Overview

Gene Information

Protein Structure and Function

Enzyme Classification and Structure

Catalytic Activity

Retinoid Metabolism

Aldehyde Detoxification

Substrate Specificity

Expression Pattern in the Brain

Regional Distribution

Cellular Distribution

Developmental Regulation

Role in Neurodegenerative Diseases

Alzheimer's Disease

Retinoid Signaling Dysregulation

Oxidative Stress

Neurogenesis

Therapeutic Implications

Parkinson's Disease

Dopaminergic Neuron Vulnerability

Retinoid Signaling

Neuroinflammation

Glioma and Brain Tumors

Cancer Stem Cells

Tumorigenesis

Therapeutic Targeting

Other Neurological Conditions

Raine Syndrome

Neuroblastoma

Epilepsy

Biological Functions Beyond Neurodegeneration

Retinoid Signaling

Development

Differentiation

Plasticity

Oxidative Stress Defense

Neuroprotection

Signaling

Interacting Partners and Pathways

Therapeutic Strategies

Targeting ALDH1A3

In Neurodegeneration

In Cancer

Challenges

Research Tools and Models

Animal Models

Cell Models

Pharmacological Tools

Cross-Linking and Related Pathways

Related Mechanisms

Related Diseases and Proteins

Related Genes

Future Directions and Research Gaps

Current Understanding

Unmet Needs

Emerging Areas

See Also

External Links

References

Pathway Diagram

💬 Discussion