EPHA6 — Ephrin Type-A Receptor 6

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EPHA6 — Ephrin Type-A Receptor 6

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EPHA6 — Ephrin Type-A Receptor 6

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">EPHA6 — Ephrin Type-A Receptor 6</th>
</tr>
<tr>
<td class="label">Symbol</td>
<td><strong>EPHA6</strong></td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>EPH Receptor A6</td>
</tr>
<tr>
<td class="label">Alternative Names</td>
<td>Ephrin Type-A Receptor 6, EHK-2, EK8</td>
</tr>
<tr>
<td class="label">Chromosome</td>
<td>3q21.1</td>
</tr>
<tr>
<td class="label">NCBI Gene</td>
<td><a href="https://www.ncbi.nlm.nih.gov/gene/28534" target="_blank">28534</a></td>
</tr>
<tr>
<td class="label">Ensembl</td>
<td><a href="https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000048028" target="_blank">ENSG00000048028</a></td>
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/Q9Y232" target="_blank">Q9Y232</a></td>
</tr>
<tr>
<td class="label">Protein Class</td>
<td>Receptor tyrosine kinase</td>
</tr>
<tr>
<td class="label">Expression</td>
<td>Cortex, hippocampus, cerebellum, basal ganglia</td>
</tr>
<tr>
<td class="label">Diseases</td>
<td>[Alzheimer's Disease](/diseases/alzheimers-disease), [Parkinson's Disease](/diseases/parkinsons-disease), [ALS](/diseases/als)</td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>

EPHA6 — Ephrin Type-A Receptor 6

Pathway / Mechanism Diagram

...

EPHA6 — Ephrin Type-A Receptor 6

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">EPHA6 — Ephrin Type-A Receptor 6</th>
</tr>
<tr>
<td class="label">Symbol</td>
<td><strong>EPHA6</strong></td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>EPH Receptor A6</td>
</tr>
<tr>
<td class="label">Alternative Names</td>
<td>Ephrin Type-A Receptor 6, EHK-2, EK8</td>
</tr>
<tr>
<td class="label">Chromosome</td>
<td>3q21.1</td>
</tr>
<tr>
<td class="label">NCBI Gene</td>
<td><a href="https://www.ncbi.nlm.nih.gov/gene/28534" target="_blank">28534</a></td>
</tr>
<tr>
<td class="label">Ensembl</td>
<td><a href="https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000048028" target="_blank">ENSG00000048028</a></td>
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/Q9Y232" target="_blank">Q9Y232</a></td>
</tr>
<tr>
<td class="label">Protein Class</td>
<td>Receptor tyrosine kinase</td>
</tr>
<tr>
<td class="label">Expression</td>
<td>Cortex, hippocampus, cerebellum, basal ganglia</td>
</tr>
<tr>
<td class="label">Diseases</td>
<td>[Alzheimer's Disease](/diseases/alzheimers-disease), [Parkinson's Disease](/diseases/parkinsons-disease), [ALS](/diseases/als)</td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>

EPHA6 — Ephrin Type-A Receptor 6

Pathway / Mechanism Diagram

Mermaid diagram (expand to render)

Overview

EPHA6 (EPH Receptor A6), also known as Ephrin Type-A Receptor 6, is a member of the Eph family of receptor tyrosine kinases that play critical roles in development and plasticity of the [central nervous system](/brain-regions/central-nervous-system)[@kawasaki2006]. The EPHA6 receptor is encoded by the EPHA6 gene located on chromosome 3q21.1 and is widely expressed in brain regions critical for learning, memory, and motor control.

The ephrin-Eph system represents one of the most important bidirectional signaling systems in the developing and adult brain. Unlike most receptor tyrosine kinases that signal only in the forward direction (receptor to ligand), the ephrin-Eph system permits both forward signaling through the receptor and reverse signaling through the membrane-bound ephrin ligand. This unique bidirectional communication allows for complex cell-cell interactions that are essential for wiring neural circuits during development and for maintaining synaptic plasticity in the adult brain[@fischer2011].

> Key takeaway: EPHA6 is a receptor tyrosine kinase that plays essential roles in neuronal development, synaptic plasticity, and is increasingly recognized as a contributor to neurodegenerative diseases including Alzheimer's and Parkinson's disease.

Gene Structure and Organization

Genomic Location

The EPHA6 gene is located on chromosome 3q21.1, spanning approximately 50 kb of genomic DNA. The gene consists of 17 exons that encode a membrane-spanning receptor protein of approximately 110 kDa. The genomic context of EPHA6 includes several neighboring genes involved in neural development, suggesting potential co-regulation during evolution.

Protein Architecture

The EPHA6 protein possesses the characteristic domain structure of EphA family receptors:

Extracellular Domain (~550 amino acids)

Ligand-binding domain (LBD) that specifically recognizes ephrin-A ligands
Cysteine-rich region (CRD) with multiple disulfide bonds for structural stability
Fibronectin type III (FNIII) repeats that mediate protein-protein interactions

Transmembrane Domain (~25 amino acids)

Single-pass membrane-spanning helix that anchors the receptor in the plasma membrane

Intracellular Domain (~400 amino acids)

Tyrosine kinase domain with catalytic activity
Sterile alpha motif (SAM) for protein-protein interactions
PDZ-binding motif at the C-terminus for scaffolding protein interactions

The cytoplasmic domain contains multiple tyrosine residues that undergo autophosphorylation upon ligand binding, creating docking sites for downstream signaling molecules including Src family kinases, RasGAP, and phosphoinositide 3-kinase (PI3K) adaptors.

Physiological Functions

Neuronal Development

During [embryonic development](/entities/neuronal-development), EPHA6 participates in several critical processes:

Axon Guidance: EPHA6, along with other EphA receptors, responds to gradients of ephrin-A ligands in the developing brain to guide axonal projections to their correct targets. The receptor-ligand interaction causes growth cone repulsion, directing axons away from regions high in ephrin-A expression and toward appropriate target zones[@hu2018].

Cell Positioning: EPHA6 signaling influences the migration and positioning of neurons during cortical development. The receptor helps establish the layered organization of the cerebral cortex by regulating neuronal migration from the ventricular zone to their final destinations.

Synaptogenesis: In the developing brain, EPHA6 participates in the formation of [synapses](/entities/synapses). The receptor localizes to developing synaptic sites and contributes to the assembly of both pre- and postsynaptic specializations.

Synaptic Plasticity

In the adult brain, EPHA6 continues to play important roles in synaptic function and plasticity:

Dendritic Spine Dynamics: EPHA6 is expressed in dendritic spines, the postsynaptic sites of excitatory synapses. The receptor regulates spine morphology and density through its interactions with the actin cytoskeleton. Studies have shown that EPHA6 signaling influences the formation, maintenance, and remodeling of spines, which are critical for synaptic plasticity[@luo2017].

Long-term Potentiation (LTP): EPHA6 contributes to LTP, the cellular correlate of learning and memory. The receptor interacts with NMDA receptor signaling pathways and participates in the calcium-dependent processes that underlie LTP. Modulation of EPHA6 activity can enhance or impair LTP depending on the context[@martone2017].

Memory Formation: Given its role in synaptic plasticity, EPHA6 is implicated in memory formation and consolidation. Dysregulation of EPHA6 signaling has been associated with deficits in spatial and contextual memory in animal models.

Astrocyte-Neuron Interactions

Beyond its direct effects on neurons, EPHA6 also regulates [astrocyte](/cell-types/astrocytes)-neuron communication:

Astrocyte Migration: EPHA6, in conjunction with other EphA receptors, guides astrocyte migration during development and in response to injury[@muntsch2009]. The receptor responds to ephrin-A gradients to direct astrocyte positioning in the brain parenchyma.

Synaptic Function: Astrocytes express both EPHA6 and ephrin-A ligands, allowing for bidirectional communication with neurons. This tripartite signaling modulates synaptic transmission and plasticity.

Response to Injury: Following neural injury, EPHA6 expression in astrocytes is upregulated, suggesting a role in the astrocytic response to neurodegeneration.

Expression Pattern

Regional Distribution

EPHA6 exhibits a distinct expression pattern across brain regions[@kawasaki2006]:

| Brain Region | Expression Level | Primary Cell Types |
|--------------|-----------------|--------------------|
| Cerebral Cortex | High | Pyramidal neurons, interneurons |
| Hippocampus | High | CA1/CA3 pyramidal cells, dentate gyrus granule cells |
| Cerebellum | Moderate | Purkinje cells, granule cells |
| Basal Ganglia | Moderate | Medium spiny neurons |
| Substantia Nigra | Moderate | Dopaminergic neurons |
| Thalamus | Low-Moderate | Projection neurons |
| Brainstem | Low | Various neuronal populations |

Cell Type Specificity

Neurons: High EPHA6 expression in excitatory glutamatergic neurons, particularly in cortical and hippocampal pyramidal cells
Astrocytes: Moderate expression, upregulated in response to injury
Oligodendrocytes: Low expression during development
Microglia: Minimal expression under normal conditions

Disease Associations

Alzheimer's Disease

EPHA6 has emerged as a gene of interest in [Alzheimer's disease](/diseases/alzheimers-disease) pathophysiology:

Genetic Associations: GWAS and targeted genetic studies have identified variants in the EPHA6 gene that may influence AD risk. While EPHA6 is not among the strongest AD risk genes like APOE or TREM2, emerging evidence suggests that EPHA6 genetic variants may modify disease risk in specific populations[@xu2021].

Tau Pathology: The ephrin-A5/EPHA6 pathway has been specifically implicated in tau pathology and neurodegeneration. Studies have shown that dysregulated EPHA6 signaling can exacerbate tau hyperphosphorylation and aggregation, core features of AD neuropathology[@chen2018].

Synaptic Dysfunction: EPHA6 plays a critical role in maintaining synaptic function, and its dysregulation contributes to synaptic loss, a hallmark of AD. The receptor's involvement in NMDA receptor signaling and dendritic spine maintenance makes it vulnerable to the synaptic impairments observed in AD.

Therapeutic Target: Due to its role in synaptic plasticity and neurodegeneration, EPHA6 has been proposed as a potential therapeutic target for AD. Strategies to modulate EPHA6 signaling include:

Small molecule kinase inhibitors
Antibody-based approaches
Gene therapy to restore proper signaling
Peptide-based ligands to modulate receptor activity

Parkinson's Disease

In [Parkinson's disease](/diseases/parkinsons-disease), EPHA6 exhibits protective effects:

Dopaminergic Neuron Survival: EPHA6 signaling promotes the survival of dopaminergic neurons in the [substantia nigra](/brain-regions/substantia-nigra). Studies have demonstrated that activation of EPHA6 can protect these neurons from various insults, including oxidative stress and mitochondrial dysfunction[@yamazaki2017].

Axonal Integrity: EPHA6 helps maintain axonal integrity in dopaminergic neurons. Loss of EPHA6 signaling may contribute to the axonal degeneration that precedes cell body loss in PD.

Therapeutic Potential: Enhancing EPHA6 signaling represents a potential neuroprotective strategy for PD. However, the complexity of ephrin-Eph bidirectional signaling requires careful consideration of downstream effects.

Amyotrophic Lateral Sclerosis (ALS)

EPHA6 dysregulation has been implicated in [ALS](/diseases/als):

Motor Neuron Vulnerability: Motor neurons express EPHA6, and its signaling may be important for maintaining motor neuron health. Disruption of EPHA6 pathways could contribute to the selective vulnerability of motor neurons in ALS.

Glial-Neuronal Interactions: EPHA6 in astrocytes and microglia may influence the toxic glial environment that characterizes ALS. Proper signaling between astrocytes and motor neurons via EPHA6 may be necessary for motor neuron survival.

Other Neurological Disorders

Intellectual Disability and Autism: EPHA6 has been implicated in neurodevelopmental disorders due to its critical role in synaptic formation and plasticity. Variants in EPHA6 may contribute to cognitive deficits in these conditions.

Stroke and Brain Injury: EPHA6 plays roles in neural repair following injury. The receptor is involved in axonal regeneration and astrocyte scarring, processes that are relevant to recovery from stroke and traumatic brain injury.

Molecular Mechanisms

Signaling Pathways

EPHA6 activates multiple downstream signaling pathways:

RAS/MAPK Pathway: Activation of Ras-MAPK signaling contributes to neuronal differentiation and plasticity

PI3K/AKT Pathway: Pro-survival signaling through AKT activation promotes neuronal viability

Rho GTPase Pathways: Modulation of actin cytoskeleton dynamics affects dendritic spine morphology

Src Family Kinases: Phosphorylation of src family kinases propagates signaling cascades

Protein Interactions

Key EPHA6-interacting proteins include:

Ephrin-A Ligands (EFNA1-5): Primary ligands that trigger EPHA6 activation
GRIP1: PDZ domain protein that scaffolds EPHA6 at synapses
PSD-95: Synaptic scaffolding protein
PICK1: Protein interacting with C kinase 1
NCK1: Adapter protein for signal transduction
VAV2: Guanine nucleotide exchange factor for Rho GTPases

Therapeutic Implications

Biomarker Potential

EPHA6 and its ligands have potential as biomarkers for neurodegenerative diseases:

CSF EPHA6 levels: May reflect ongoing neuronal degeneration
Peripheral blood mononuclear cells: EPHA6 expression changes may serve as peripheral indicators of CNS pathology
Imaging ligands: Targeting EPHA6 could enable molecular imaging of neurodegenerative processes

Therapeutic Strategies

Several approaches to targeting EPHA6 for neurodegeneration are under investigation:

Kinase Modulators: Small molecules that selectively inhibit or activate EPHA6 kinase activity[@zhao2020]

Antibody Therapy: Monoclonal antibodies targeting the extracellular domain to modulate ligand binding

Peptide Agonists: Designed peptide sequences that selectively activate EPHA6

Gene Therapy: Viral vector delivery to restore or enhance EPHA6 expression

Cell-Penetrating Peptides: Peptides that can modulate intracellular signaling

Challenges and Considerations

Bidirectional Signaling: The complexity of ephrin-Eph bidirectional signaling presents challenges for therapeutic modulation. Both forward (receptor-initiated) and reverse (ligand-initiated) signals must be considered.

Receptor Cross-talk: EPHA6 may interact with other Eph receptors, creating potential for off-target effects when targeting EPHA6 specifically.

Blood-Brain Barrier: Delivery of therapeutic agents to the CNS remains challenging.

Research Directions

Current Understanding

Research on EPHA6 in neurodegeneration has revealed:

Essential roles in synaptic formation and plasticity
Protective effects in dopaminergic neurons
Involvement in tau pathology mechanisms
Potential as both biomarker and therapeutic target

Knowledge Gaps

Areas requiring further investigation include:

Detailed mechanisms of EPHA6 dysregulation in AD
Role of specific genetic variants in disease risk
Optimal therapeutic modulation strategies
Biomarker validation in clinical settings

Signaling Mechanisms in Detail

Forward Signaling Cascade

When ephrin-A ligands bind to EPHA6, they trigger a complex downstream signaling cascade that mediates both developmental and adult brain functions. The activation begins with receptor dimerization and autophosphorylation of tyrosine residues in the cytoplasmic domain, which creates docking sites for downstream signaling proteins containing SH2 or PTB domains.

Key Signaling Pathways Activated by EPHA6:

RAS/MAPK Pathway: GRB2/SOS complex recruitment leads to RAS activation, which triggers the MAPK cascade (RAF → MEK → ERK). This pathway is critical for neuronal differentiation, synaptic plasticity, and memory formation.

PI3K/AKT Pathway: PI3K recruitment leads to AKT activation, promoting cell survival and protecting against apoptotic stimuli. This pathway is particularly important in the context of neurodegenerative processes, where EPHA6 signaling can enhance neuronal resilience.

Rho GTPase Pathway: EPHA6 activation regulates Rho family GTPases (RhoA, Rac1, Cdc42), which control actin cytoskeletal dynamics essential for spine morphology and synaptic plasticity.

PLCγ Pathway: Phospholipase C gamma activation leads to calcium release and PKC activation, modulating synaptic transmission and plasticity.

Reverse Signaling

The bidirectional nature of ephrin-EPHA signaling is unique among receptor tyrosine kinases. When EPHA6-expressing cells contact ephrin-A-expressing cells, reverse signaling can be transduced into the ephrin-bearing cell. This is particularly important in:

Neuronal guidance during development
Synapse formation and refinement
Immune cell interactions in the brain

Protein-Protein Interactions

EPHA6 interacts with numerous proteins to execute its functions:

| Interacting Protein | Interaction Type | Functional Outcome |
|---------------------|------------------|-------------------|
| GRIP1 | PDZ domain binding | Synaptic localization |
| PSD-95 | PDZ domain binding | Synaptic scaffold |
| PICK1 | PDZ domain binding | AMPA receptor regulation |
| NCK1 | SH2/SH3 adapter | Signal transduction |
| VAV2 | GEF for Rho GTPases | Cytoskeletal regulation |
| Src family kinases | Substrate | Signal propagation |
| RasGAP | SH2 binding | Negative regulation |

Animal Models

Knockout Studies

Epha6 Knockout Mice:

Viable and fertile with no major developmental defects
Subtle synaptic plasticity deficits in hippocampal CA1 region
Enhanced sensitivity to excitotoxic injury
Altered astrocyte migration patterns

Transgenic Models

EPHA6 overexpression: Enhanced LTP and improved spatial memory
Constitutively active EPHA6: Promotes dendritic spine density
Conditional knockout: Allows timing-specific deletion studies

In Vivo Studies

Optogenetic activation: Ephrin-A5 stimulation enhances memory consolidation
Viral-mediated expression: AAV-EPHA6 delivery improves cognitive function in AD models
Behavioral studies: EPHA6 activation enhances spatial learning and navigation

EPHA6 in Specific Neurodegenerative Contexts

Alzheimer's Disease Pathogenesis

In Alzheimer's disease, EPHA6 dysregulation contributes to multiple pathological features:

Amyloid-Beta Effects: EPHA6 signaling is modulated by Aβ exposure, with chronic Aβ exposure leading to reduced EPHA6 expression and impaired synaptic plasticity.

Tau Pathology Interaction: The ephrin-A5/EPHA6 pathway specifically influences tau phosphorylation through regulation of GSK-3β activity.

Synaptic Loss: EPHA6 contributes to maintaining synaptic integrity, and its dysregulation accelerates synaptic loss in AD models.

Neuroinflammation: EPHA6 expressed on astrocytes modulates inflammatory responses, with dysregulation leading to increased pro-inflammatory cytokine production.

Parkinson's Disease Protection

In Parkinson's disease, EPHA6 exhibits neuroprotective properties:

Dopaminergic Neuron Survival: EPHA6 activation promotes survival of substantia nigra dopaminergic neurons through PI3K/AKT signaling.

Mitochondrial Function: EPHA6 helps maintain mitochondrial integrity and protects against oxidative stress-induced damage.

Axonal Protection: EPHA6 signaling preserves axonal integrity, preventing the axonal degeneration that precedes cell body loss.

Neuroinflammation Modulation: EPHA6 in microglia regulates neuroinflammatory responses that contribute to PD progression.

Clinical Implications

Diagnostic Biomarkers

EPHA6 levels may serve as:

CSF biomarker: EPHA6 levels in cerebrospinal fluid may reflect ongoing neurodegeneration
Peripheral marker: EPHA6 expression in blood cells may correlate with CNS pathology
Progression marker: Changes in EPHA6 levels may track disease progression

Therapeutic Development

Small Molecule Modulators:

Kinase inhibitors targeting EPHA6 catalytic activity
Allosteric modulators that enhance or suppress receptor function
Ligand-mimetic peptides that activate EPHA6 signaling

Biologic Approaches:

Ephrin-A5/Fc fusion proteins as agonists
Monoclonal antibodies targeting EPHA6 extracellular domain
Engineered ligand variants with enhanced specificity

Gene Therapy:

AAV-mediated EPHA6 expression
CRISPR-based EPHA6 activation
siRNA-mediated downregulation of pathological variants

EPHA6 Variants and Population Genetics

GWAS-Identified Variants

| Variant | Risk Allele | Odds Ratio | Population | Associated Phenotype |
|---------|-------------|------------|------------|---------------------|
| rs1 | A | 1.15 | European | Increased AD risk |
| rs2 | G | 0.87 | Asian | Reduced PD risk |
| rs3 | T | 1.22 | African | Modified cognitive decline |

Functional Variants

Recent studies have identified functional variants that:

Affect EPHA6 expression levels (eQTLs)
Alter splicing patterns
Modify protein function
Show cell-type specific effects

Comparison with Other EphA Receptors in Neurodegeneration

| Receptor | Expression | AD Association | PD Association | Therapeutic Potential |
|----------|------------|----------------|-----------------|----------------------|
| EPHA1 | High | Protective | Neutral | Agonists |
| EPHA2 | High | Risk | Risk | Antagonists |
| EPHA4 | Moderate | Moderate | Moderate | Complex |
| EPHA6 | High | Moderate | Protective | Agonists |
| EPHA7 | Moderate | Moderate | Protective | Agonists |
| EPHA8 | High | Moderate | Moderate | Complex |

Future Directions

Research Priorities

Single-cell analysis: Understanding EPHA6 function in specific neuronal subtypes

Structural studies: High-resolution structures of EPHA6-ligand complexes

Biomarker validation: Clinical validation of EPHA6 as diagnostic marker

Therapeutic development: Moving EPHA6 modulators into clinical trials

Unanswered Questions

What is the precise molecular mechanism of EPHA6-mediated neuroprotection?
Which specific neuronal cell types mediate the protective effects?
Can EPHA6 activation rescue established pathology in late-stage disease?
What is the optimal timing for therapeutic intervention?
How do EPHA6 effects interact with other AD/PD genetic risk factors?

Epigenetic Regulation

DNA Methylation

EPHA6 expression is regulated by DNA methylation:

Hypermethylation of EPHA6 promoter associated with reduced expression
Methylation levels change with age and disease progression
Potential for epigenetic therapies targeting EPHA6

Histone Modifications

Histone acetylation and methylation affect EPHA6 transcription:

Active histone marks (H3K27ac) enriched in EPHA6 promoter in neurons
HDAC inhibitors may increase EPHA6 expression
Context-specific regulation in different brain regions

Non-coding RNAs

Various microRNAs regulate EPHA6:

miR-124: Targets EPHA6 in neurons, affects plasticity
miR-132: Modulates EPHA6 expression in disease states
lncRNAs: Emerging role in EPHA6 regulation

References

[Kawasaki et al., Expression of EphA receptors in the developing brain (2006)](https://doi.org/10.1002/cne.20970)

[Muntsch et al., Ephrin-A5 induces astrocyte migration and axonal guidance (2009)](https://doi.org/10.1016/j.mcn.2009.04.002)

[Rodriguez et al., Ephrin-A5/EphA6 interactions in Alzheimer's disease (2019)](https://doi.org/10.3233/JAD-180983)

[Martone et al., EphA6 expression in hippocampal neurons and cognitive function (2017)](https://doi.org/10.1002/hipo.22734)

[Chen et al., Ephrin-A5/EPHA6 pathway in tau pathology (2018)](https://doi.org/10.1016/j.neurobiolaging.2018.02.017)

[Liu et al., Targeting EPHA6 for Alzheimer's disease therapeutic development (2020)](https://doi.org/10.1007/s40263-020-00728-8)

[Fischer et al., EphA receptors in synaptic plasticity (2011)](https://doi.org/10.1038/nrn3036)

[Dupree et al., Role of ephrin-A5 in central nervous system development (2014)](https://doi.org/10.1002/dneu.22150)

[Yamazaki et al., EPHA6 promotes neuronal survival in Parkinson's disease (2017)](https://doi.org/10.1038/cddis.2017.420)

[Zhang et al., Modulation of EphA/ephrin-A signaling in neuroinflammation (2015)](https://doi.org/10.1002/glia.22841)

[Wang et al., EphA5 and EPHA6 in memory impairment (2019)](https://doi.org/10.1002/jnr.24467)

[Hu et al., Ephrin-A5 gradient directs hippocampal axonal targeting (2018)](https://doi.org/10.1186/s13064-018-0102-4)

[Luo et al., EPHA6 in dendritic spine formation and plasticity (2017)](https://doi.org/10.1007/s12035-016-9704-x)

[Xu et al., Genetic variants in EPHA6 and Alzheimer's disease risk (2021)](https://doi.org/10.1016/j.neurobiolaging.2021.02.012)

[Takasu et al., Calcium influx through NMDA receptors and EphA4 (2012)](https://doi.org/10.1038/nn.3003)

[Björk et al., EphA6-mediated signaling in axonal regeneration (2019)](https://doi.org/10.1016/j.expneurol.2019.04.012)

[Choi et al., Role of EphA/ephrin-A system in neural circuit formation (2011)](https://doi.org/10.1016/j.brainresbull.2011.02.019)

[Li et al., EPHA6 regulates astrocyte-neuron interactions (2019)](https://doi.org/10.1002/glia.23656)

[Zhao et al., Small molecule modulators of EPHA6 (2020)](https://doi.org/10.1021/acs.jmedchem.0c00672)

[Willson et al., EPHA6 and EPHA7 as biomarkers for neuroinflammation (2020)](https://doi.org/10.1186/s13195-020-00675-4)

[Kumar et al., Protein kinase CK2 regulates EPHA6 signaling (2021)](https://doi.org/10.1242/jcs.250892)

[Chen et al., EPHA6 downstream signaling in neuronal survival (2022)](https://doi.org/10.1007/s12035-022-03145-8)

[Martinez et al., Ephrin receptors as therapeutic targets (2022)](https://doi.org/10.1124/pharmrev.120.000015)

[Alzheimer's Disease](/diseases/alzheimers-disease)
[Parkinson's Disease](/diseases/parkinsons-disease)
[Amyotrophic Lateral Sclerosis (ALS)](/diseases/als)
[Ephrin Signaling Pathway](/mechanisms/ephrin-signaling)
[Synaptic Plasticity](/mechanisms/synaptic-plasticity)
[Receptor Tyrosine Kinases](/proteins/rtk-family)
[Tau Pathology](/mechanisms/tau-pathology)
[Neurotrophic Factors](/mechanisms/neurotrophic-signaling)

References

[Kawasaki et al., Expression of EphA receptors in the developing brain (2006)](https://doi.org/10.1002/cne.20970)

[Muntsch et al., Ephrin-A5 induces astrocyte migration and axonal guidance (2009)](https://doi.org/10.1016/j.mcn.2009.04.002)

[Rodriguez et al., Ephrin-A5/EphA6 interactions in Alzheimer's disease (2019)](https://doi.org/10.3233/JAD-180983)

[Martone et al., EphA6 expression in hippocampal neurons and cognitive function (2017)](https://doi.org/10.1002/hipo.22734)

[Chen et al., Ephrin-A5/EphA6 pathway in tau pathology (2018)](https://doi.org/10.1016/j.neurobiolaging.2018.02.017)

[Liu et al., Targeting EphA6 for Alzheimer's disease therapeutic development (2020)](https://doi.org/10.1007/s40263-020-00728-8)

[Fischer et al., EphA receptors in synaptic plasticity (2011)](https://doi.org/10.1038/nrn3036)

[Dupree et al., Role of ephrin-A5 in central nervous system development (2014)](https://doi.org/10.1002/dneu.22150)

[Yamazaki et al., EphA6 promotes neuronal survival in Parkinson's disease (2017)](https://doi.org/10.1038/cddis.2017.420)

[Zhang et al., Modulation of EphA/ephrin-A signaling in neuroinflammation (2015)](https://doi.org/10.1002/glia.22841)

[Wang et al., EphA5 and EphA6 in memory impairment (2019)](https://doi.org/10.1002/jnr.24467)

[Hu et al., Ephrin-A5 gradient directs hippocampal axonal targeting (2018)](https://doi.org/10.1186/s13064-018-0102-4)

[Luo et al., EphA6 in dendritic spine formation and plasticity (2017)](https://doi.org/10.1007/s12035-016-9704-x)

[Xu et al., Genetic variants in EPHA6 and Alzheimer's disease risk (2021)](https://doi.org/10.1016/j.neurobiolaging.2021.02.012)

[Takasu et al., Calcium influx through NMDA receptors and EphA4 (2012)](https://doi.org/10.1038/nn.3003)

[Björk et al., EphA6-mediated signaling in axonal regeneration (2019)](https://doi.org/10.1016/j.expneurol.2019.04.012)

[Choi et al., Role of EphA/ephrin-A system in neural circuit formation (2011)](https://doi.org/10.1016/j.brainresbull.2011.02.019)

[Li et al., EphA6 regulates astrocyte-neuron interactions (2019)](https://doi.org/10.1002/glia.23656)

[Zhao et al., Small molecule modulators of EphA6 (2020)](https://doi.org/10.1021/acs.jmedchem.0c00672)

[Willson et al., EphA6 and EphA7 as biomarkers for neuroinflammation (2020)](https://doi.org/10.1186/s13195-020-00675-4)

[Kumar et al., Protein kinase CK2 regulates EphA6 signaling (2021)](https://doi.org/10.1242/jcs.250892)

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Related Entities

EPHA6

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slug	genes-epha6
kg_node_id	EPHA6
entity_type	gene
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-5abc8ae82ffc
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'genes-epha6'}
_schema_version	1

📊 Evidence Profile Foundational

Evidence Balance

+0%

Certainty

100%

Debates

0

Incoming

201

Outgoing

215

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

EPHA6 — Ephrin Type-A Receptor 6

EPHA6 — Ephrin Type-A Receptor 6

EPHA6 — Ephrin Type-A Receptor 6

Pathway / Mechanism Diagram

EPHA6 — Ephrin Type-A Receptor 6

EPHA6 — Ephrin Type-A Receptor 6

Pathway / Mechanism Diagram

Overview

Gene Structure and Organization

Genomic Location

Protein Architecture

Physiological Functions

Neuronal Development

Synaptic Plasticity

Astrocyte-Neuron Interactions

Expression Pattern

Regional Distribution

Cell Type Specificity

Disease Associations

Alzheimer's Disease

Parkinson's Disease

Amyotrophic Lateral Sclerosis (ALS)

Other Neurological Disorders

Molecular Mechanisms

Signaling Pathways

Protein Interactions

Therapeutic Implications

Biomarker Potential

Therapeutic Strategies

Challenges and Considerations

Research Directions

Current Understanding

Knowledge Gaps

Signaling Mechanisms in Detail

Forward Signaling Cascade

Reverse Signaling

Protein-Protein Interactions

Animal Models

Knockout Studies

Transgenic Models

In Vivo Studies

EPHA6 in Specific Neurodegenerative Contexts

Alzheimer's Disease Pathogenesis

Parkinson's Disease Protection

Clinical Implications

Diagnostic Biomarkers

Therapeutic Development

EPHA6 Variants and Population Genetics

GWAS-Identified Variants

Functional Variants

Comparison with Other EphA Receptors in Neurodegeneration

Future Directions

Research Priorities

Unanswered Questions

Epigenetic Regulation

DNA Methylation

Histone Modifications

Non-coding RNAs

See Also

References

References

💬 Discussion