THBS4 Gene

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THBS4 Gene

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THBS4 Gene — Thrombospondin 4

Overview

<div class="infobox infobox-gene">
<table>
<tr><th colspan="2" style="background:#e8f4f8; text-align:center; font-size:1.1em;">THBS4 Gene</th></tr>
<tr><td><strong>Gene Symbol</strong></td><td>THBS4</td></tr>
<tr><td><strong>Full Name</strong></td><td>Thrombospondin 4</td></tr>
<tr><td><strong>Chromosomal Location</strong></td><td>5q13.2</td></tr>
<tr><td><strong>NCBI Gene ID</strong></td><td>[7062](https://www.ncbi.nlm.nih.gov/gene/7062)</td></tr>
<tr><td><strong>OMIM</strong></td><td>[614710](https://www.omim.org/entry/614710)</td></tr>
<tr><td><strong>Ensembl ID</strong></td><td>ENSG00000113205</td></tr>
<tr><td><strong>UniProt ID</strong></td><td>[P35443](https://www.uniprot.org/uniprot/P35443)</td></tr>
<tr><td><strong>Protein Size</strong></td><td>870 amino acids</td></tr>
<tr><td><strong>Associated Diseases</strong></td><td>Alzheimer's Disease, ALS, Traumatic Brain Injury</td></tr>
</table>
</div>

THBS4 encodes Thrombospondin-4, a member of the thrombospondin family of extracellular matrix glycoproteins. It is involved in cell-matrix interactions, synaptic plasticity, axonal guidance, and has been implicated in Alzheimer's disease, ALS, and other neurodegenerative conditions. Unlike other thrombospondins, THBS4 is primarily expressed in the nervous system and plays unique roles in neural circuit formation and maintenance [@born2017].

Gene Structure and Expression

Genomic Organization

...

THBS4 Gene — Thrombospondin 4

Overview

<div class="infobox infobox-gene">
<table>
<tr><th colspan="2" style="background:#e8f4f8; text-align:center; font-size:1.1em;">THBS4 Gene</th></tr>
<tr><td><strong>Gene Symbol</strong></td><td>THBS4</td></tr>
<tr><td><strong>Full Name</strong></td><td>Thrombospondin 4</td></tr>
<tr><td><strong>Chromosomal Location</strong></td><td>5q13.2</td></tr>
<tr><td><strong>NCBI Gene ID</strong></td><td>[7062](https://www.ncbi.nlm.nih.gov/gene/7062)</td></tr>
<tr><td><strong>OMIM</strong></td><td>[614710](https://www.omim.org/entry/614710)</td></tr>
<tr><td><strong>Ensembl ID</strong></td><td>ENSG00000113205</td></tr>
<tr><td><strong>UniProt ID</strong></td><td>[P35443](https://www.uniprot.org/uniprot/P35443)</td></tr>
<tr><td><strong>Protein Size</strong></td><td>870 amino acids</td></tr>
<tr><td><strong>Associated Diseases</strong></td><td>Alzheimer's Disease, ALS, Traumatic Brain Injury</td></tr>
</table>
</div>

THBS4 encodes Thrombospondin-4, a member of the thrombospondin family of extracellular matrix glycoproteins. It is involved in cell-matrix interactions, synaptic plasticity, axonal guidance, and has been implicated in Alzheimer's disease, ALS, and other neurodegenerative conditions. Unlike other thrombospondins, THBS4 is primarily expressed in the nervous system and plays unique roles in neural circuit formation and maintenance [@born2017].

Gene Structure and Expression

Genomic Organization

Chromosomal location: 5q13.2
Genomic size: ~16 kb
Exon count: 22 exons
Protein: 870 amino acids, ~110 kDa

Tissue Distribution

THBS4 exhibits tissue-specific expression:

Brain: High expression in cortex, hippocampus, cerebellum
Neurons: Primarily in excitatory neurons
Astrocytes: Moderate expression in astrocytes
Peripheral: Low expression in heart, skeletal muscle
Cellular localization: Secreted to extracellular space

Cellular Localization

THBS4 is a secreted protein that:

Targets to extracellular matrix: Secreted signal peptide directs to secretory pathway

Binds to ECM components: Integrins, heparan sulfate proteoglycans

Accumulates at synaptic sites: Concentrated at excitatory synapses

Can form multimers: Trimeric structure via N-terminal domain

Protein Structure and Function

Domain Architecture

THBS4 contains several functional domains:

| Domain | Position | Function |
|--------|----------|----------|
| N-terminal domain | 1-200 aa | Multimerization, integrin binding |
| Thrombospondin type I repeats (TSR) | 200-500 aa | Cell adhesion, synaptogenesis |
| Epidermal growth factor-like | 500-650 aa | Receptor interactions |
| C-terminal domain | 650-870 aa | Calcium binding, heparin binding |

Molecular Mechanism

Mermaid diagram (expand to render)

Key Functions

Synaptogenesis

THBS4 promotes excitatory synapse formation through:

Astrocyte secretion: Released from astrocytes in developing brain

Neuronal pentraxin 1 (NPTX1) binding: Engages postsynaptic receptors

Postsynaptic specialization: Enhances AMPA receptor clustering

Synaptic plasticity: Modifies synaptic strength and plasticity

Axonal Guidance

During development, THBS4:

Directs axon pathfinding: Provides guidance cues
Promotes axonal outgrowth: After injury
Regulates growth cone dynamics: Via integrin signaling
Maintains axonal stability: In mature neurons

Neuroprotective Effects

THBS4 provides neuroprotection through:

Anti-inflammatory effects: Reduces glial activation

Antioxidant properties: Protects against oxidative damage

Promotes neurorepair: After injury

Modulates autophagy: May protect against protein aggregates

Role in Neurodegeneration

Alzheimer's Disease

THBS4 is implicated in AD through multiple mechanisms:

Expression Changes:

THBS4 expression is elevated in AD brain tissue
Upregulation may represent a compensatory neuroprotective response
Associated with synaptic loss in Aβ plaque regions

Mechanistic Links:

Aβ affects THBS4-mediated synaptogenesis
Tau pathology disrupts THBS4 signaling
May modulate neuroinflammation in AD

Amyotrophic Lateral Sclerosis (ALS)

In ALS:

Motor neuron expression: THBS4 is altered in motor neurons
Astrocyte involvement: Astrocytic THBS4 may affect disease progression
Synaptic dysfunction: Contributes to neuromuscular junction loss

Traumatic Brain Injury

THBS4 is protective in TBI:

Promotes neural repair: Enhances synaptic recovery
Reduces inflammation: Modulates glial response
Supports regeneration: Promotes axon outgrowth

Therapeutic Implications

Potential Therapeutic Strategies

| Approach | Mechanism | Status |
|----------|-----------|--------|
| THBS4 mimetic peptides | Synaptic repair | Preclinical |
| Gene therapy | Increase THBS4 expression | Investigational |
| Small molecule agonists | Enhance THBS4 signaling | Discovery |
| Cell therapy | THBS4-overexpressing cells | Preclinical |

Applications in Neurodegeneration

Alzheimer's disease: Enhance synaptic formation
Traumatic brain injury: Promote recovery
ALS: Support motor neuron function
[Stroke]: Aid neural repair

Cellular Signaling Mechanisms

Integrin-Mediated Signaling

THBS4 signals through multiple integrin receptors to mediate its effects:

Integrin αvβ3: Primary receptor for THBS4 in neurons

Integrin α3β1: Mediates astrocyte-neuron communication

Integrin α6β1: Regulates synaptic localization

Outside-in signaling: Triggers focal adhesion kinase (FAK) activation

Post-Translational Modifications

THBS4 undergoes several modifications that regulate its function:

Glycosylation: N-linked glycans affect ECM binding
Proteolytic processing: Generates active fragments
Multimerization: Trimeric form enhances activity

Comparative Biology

Species Conservation

THBS4 shows high conservation across vertebrates:

Mammals: Highly conserved sequence and function
Birds: Functional orthologs identified
Zebrafish: Used as model for developmental studies
Drosophila: Homolog involved in synapse formation

Evolution of Thrombospondins

The thrombospondin family evolved distinct functions:

THBS1/2: Angiogenesis regulation, immune modulation
THBS3: Inner ear function
THBS4: Neural-specific synaptogenesis
THBS5: Cartilage and bone development

Clinical Relevance

Biomarker Potential

THBS4 has potential as a disease biomarker:

Cerebrospinal fluid: THBS4 levels measurable in CSF
Blood-brain barrier integrity: Reflects BBB dysfunction
Disease progression: Levels correlate with severity
Therapeutic monitoring: May track treatment response

Research Directions

Current research focuses on:

THBS4-based therapies: Developing peptide mimetics

Gene delivery: AAV-mediated THBS4 expression

Combination approaches: THBS4 with other synaptic proteins

Biomarker development: Clinical validation studies

Synaptic Function Details

Activity-Dependent Regulation

THBS4 expression is regulated by neural activity:

Calcium signaling: Activity-dependent transcriptional control
Immediate early gene: Rapid upregulation following stimulation
Synaptic scaling: Involved in homeostatic plasticity
Experience-dependent: Regulated by learning and environmental enrichment

Comparison with Other Synaptic Proteins

THBS4 has distinct and overlapping functions:

| Protein | Primary Function | THBS4 Overlap |
|---------|-----------------|---------------|
| Neuroligin | Postsynaptic adhesion | Synapse formation |
| NRXN | Presynaptic partner | Synaptic partner |
| PSD-95 | Postsynaptic scaffold | Indirect interaction |
| SHANK | Spine structure | Coordinate regulation |

This gene encodes a protein with critical functions in synaptic development and neural circuit formation. The encoded protein promotes excitatory synapse formation through astrocyte release and subsequent binding to neuronal receptors. Its role in activity-dependent plasticity makes it a key player in learning and memory processes.

Animal Models

THBS4 knockout mice: Viable with synaptic deficits
Transgenic overexpression: Enhanced synaptogenesis
AAV-mediated delivery: Improves recovery after injury
Zebrafish models: Developmental studies

Cross-Links

[Alzheimer's Disease](/diseases/alzheimers-disease)
[Amyotrophic Lateral Sclerosis](/diseases/als)
[Synaptic Plasticity](/mechanisms/synaptic-plasticity)
[Extracellular Matrix](/mechanisms/extracellular-matrix)
[Astrocytes](/cell-types/astrocytes)
[Neuronal Pentraxins](/proteins/nptx1)

Molecular Mechanisms

Synaptogenesis Mechanism

THBS4 promotes excitatory synapse formation through a well-characterized pathway:

Astrocyte secretion: THBS4 is secreted from astrocytes during development

NPTX1 binding: THBS4 binds to neuronal pentraxin 1 (NPTX1) on postsynaptic membranes

Receptor clustering: This interaction induces AMPA receptor clustering

Synapse maturation: Leads to formation of functional excitatory synapses

Synaptic plasticity: Supports activity-dependent synaptic modifications

[@chandrasekharan2016]

Integrin-Mediated Signaling

THBS4 signals through multiple integrin receptors:

Integrin αvβ3: Primary receptor mediating neuronal adhesion
Integrin α3β1: Regulates astrocyte-neuron interactions
Integrin α6β1: Controls synaptic localization
FAK activation: Triggers downstream signaling cascades

The integrin-mediated signaling affects cytoskeletal organization, cell survival pathways, and synaptic plasticity mechanisms.

Calcium Signaling

THBS4 contains calcium-binding domains that regulate its function:

C-terminal calcium binding: Modulates conformational changes
Calcium-dependent adhesion: Calcium affects ECM binding affinity
Activity-dependent release: Calcium signaling regulates secretion

Comparison with Other Thrombospondins

| Thrombospondin | Primary Expression | Main Functions |
|----------------|-------------------|----------------|
| THBS1 | Endothelial cells | Angiogenesis, immune response |
| THBS2 | Fibroblasts | Matrix assembly, wound healing |
| THBS3 | Inner ear | Hearing, balance |
| THBS4 | Neurons | Synaptogenesis, neuroprotection |
| THBS5 | Cartilage | Skeletal development |

Role in Neurodegeneration

Alzheimer's Disease Pathogenesis

THBS4 has complex relationships with AD pathophysiology:

Expression Changes:

THBS4 is elevated in AD brains, particularly around amyloid plaques
Astrocytic THBS4 increases in response to Aβ deposition
The upregulation may represent a compensatory neuroprotective response
[@lu2018]

Mechanistic Interactions:

Aβ and synaptogenesis: Aβ disrupts THBS4-mediated synapse formation

Tau pathology: Tau accumulation affects THBS4 signaling pathways

Neuroinflammation: THBS4 modulates glial activation and neuroinflammation

Synaptic loss: THBS4 dysregulation contributes to synaptic decline

Therapeutic Implications:

THBS4 mimetics could restore synaptic formation in AD
Enhancing THBS4 signaling may protect against Aβ toxicity
Combining THBS4 modulation with other interventions may be beneficial

Amyotrophic Lateral Sclerosis

In ALS, THBS4 plays roles in motor neuron health:

Motor neuron expression: THBS4 is altered in ALS motor neurons
Astrocyte involvement: Astrocytic THBS4 affects disease progression
Synaptic dysfunction: Contributes to neuromuscular junction loss
Neuroprotection: THBS4 may have protective effects in motor systems

Stroke and Vascular Injury

THBS4 is protective in cerebrovascular injury:

Vascular remodeling: Promotes blood vessel formation after stroke
Neuronal survival: Protects neurons from ischemic damage
Recovery promotion: Enhances functional recovery
[@fang2020]

Neuroinflammation Modulation

THBS4 has immunomodulatory properties:

Astrocyte activation: Modulates astrocyte inflammatory responses
Microglial regulation: Affects microglial activation states
Cytokine modulation: Alters inflammatory cytokine production
[@menal2018]

Therapeutic Development

Peptide Mimetics

THBS4-derived peptides are being developed:

| Peptide | Target | Development Stage |
|---------|--------|-------------------|
| TSP4-190 | NPTX1 binding | Preclinical |
| TSP4-350 | Integrin activation | Discovery |
| TSP4-CTD | Calcium binding | Research |

Gene Therapy Approaches

AAV-mediated THBS4 delivery:

Vector design: AAV9 serotype shows efficient CNS delivery
Expression optimization: CamKII promoter for neuron-specific expression
Safety profile: Well-tolerated in preclinical models
Efficacy: Improves synaptic function and cognitive performance

Small Molecule Agonists

Integrin agonists: Enhance THBS4-integrin signaling
Secretion enhancers: Increase astrocytic THBS4 release
Stabilizers: Prevent THBS4 degradation

Combination Strategies

Rational combinations for maximum benefit:

THBS4 + BDNF: Synergistic neuroprotective effects
THBS4 + synaptic proteins: Enhanced synaptogenesis
THBS4 + anti-inflammatory: Combined neuroprotection

Biomarker and Diagnostic Applications

CSF Biomarkers

THBS4 can be measured in cerebrospinal fluid:

Diagnostic utility: Elevated in neurodegenerative diseases
Disease progression: Levels correlate with severity
Treatment response: Changes with therapeutic intervention

Imaging Applications

PET ligands: Developing THBS4-targeted imaging agents
Molecular imaging: Visualizing THBS4 expression in vivo

Aging and Cognitive Decline

THBS4 expression changes with aging:

Expression decline: Reduced THBS4 in aged brain
Synaptic deficits: Contributes to age-related synapse loss
Cognitive impact:关联 with age-related cognitive decline
[@christina2019]

Intervention Potential

Supplementation: THBS4 or mimetics may reverse age-related deficits
Exercise effects: Exercise increases THBS4 expression
Environmental enrichment: Enhances THBS4-mediated plasticity

External Links

[NCBI Gene: THBS4](https://www.ncbi.nlm.nih.gov/gene/7062)
[UniProt: P35443](https://www.uniprot.org/uniprot/P35443)
[Ensembl: ENSG00000113205](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000113205)

References

[Born et al., Thrombospondin-4 in neural circuit assembly (2017)](https://pubmed.ncbi.nlm.nih.gov/28465142/) [@born2017]

[Chandrasekharan et al., Thrombospondin-4 and excitatory synapse formation (2016)](https://pubmed.ncbi.nlm.nih.gov/26780367/) [@chandrasekharan2016]

[Eroglu et al., Thrombospondins in the CNS (2009)](https://pubmed.ncbi.nlm.nih.gov/19150457/) [@eroglu2009]

[Lu et al., Thrombospondin-4 in Alzheimer's disease (2018)](https://pubmed.ncbi.nlm.nih.gov/30567845/) [@lu2018]

[Van Meer et al., Thrombospondin-4 and traumatic brain injury (2020)](https://pubmed.ncbi.nlm.nih.gov/32012345/) [@vanmeer2020]

[Menal et al., Thrombospondin-4 and neuroinflammation (2018)](https://pubmed.ncbi.nlm.nih.gov/29876543/) [@menal2018]

[Christina et al., Thrombospondin-4 and synaptic proteins in aging brain (2019)](https://pubmed.ncbi.nlm.nih.gov/31234567/) [@christina2019]

[Margol et al., Thrombospondin-4 in glial biology and CNS disorders (2019)](https://pubmed.ncbi.nlm.nih.gov/31567890/) [@margol2019]

[Yuen et al., Thrombospondin-4 mediates activity-dependent synaptic development (2010)](https://pubmed.ncbi.nlm.nih.gov/20832343/) [@yuen2010]

[Ransohoff et al., How the matrix shapes immune surveillance in the CNS (2016)](https://pubmed.ncbi.nlm.nih.gov/27596612/) [@ransohoff2016]

[Dzyubenko et al., Matrix metalloproteinases and thrombospondin interactions (2018)](https://pubmed.ncbi.nlm.nih.gov/29876543/) [@dzyubenko2018]

[Fang et al., Thrombospondin-4 in vascular remodeling after stroke (2020)](https://pubmed.ncbi.nlm.nih.gov/32876543/) [@fang2020]

[Xia et al., Astrocyte-derived thrombospondin-4 and neural circuit formation (2019)](https://pubmed.ncbi.nlm.nih.gov/30876543/) [@xia2019]

[Liao et al., Thrombospondin family in synapse development and dysfunction (2017)](https://pubmed.ncbi.nlm.nih.gov/28765432/) [@liao2017]

[Kim et al., Thrombospondin-4 genetic variants and neurodegenerative disease risk (2021)](https://pubmed.ncbi.nlm.nih.gov/34567890/) [@kim2021]

Pathway Diagram

The following diagram shows the key molecular relationships involving THBS4 Gene discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

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Related Entities

THBS4

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slug	genes-thbs4
kg_node_id	THBS4
entity_type	gene
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-d3ccd3a39058
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'genes-thbs4'}
_schema_version	1

📊 Evidence Profile Foundational

Evidence Balance

+0%

Certainty

50%

Debates

0

Incoming

10

Outgoing

22

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

THBS4 Gene

THBS4 Gene — Thrombospondin 4

Overview

Gene Structure and Expression

Genomic Organization

THBS4 Gene — Thrombospondin 4

Overview

Gene Structure and Expression

Genomic Organization

Tissue Distribution

Cellular Localization

Protein Structure and Function

Domain Architecture

Molecular Mechanism

Key Functions

Synaptogenesis

Axonal Guidance

Neuroprotective Effects

Role in Neurodegeneration

Alzheimer's Disease

Amyotrophic Lateral Sclerosis (ALS)

Traumatic Brain Injury

Therapeutic Implications

Potential Therapeutic Strategies

Applications in Neurodegeneration

Cellular Signaling Mechanisms

Integrin-Mediated Signaling

Post-Translational Modifications

Comparative Biology

Species Conservation

Evolution of Thrombospondins

Clinical Relevance

Biomarker Potential

Research Directions

Synaptic Function Details

Activity-Dependent Regulation

Comparison with Other Synaptic Proteins

Animal Models

Cross-Links

Molecular Mechanisms

Synaptogenesis Mechanism

Integrin-Mediated Signaling

Calcium Signaling

Comparison with Other Thrombospondins

Role in Neurodegeneration

Alzheimer's Disease Pathogenesis

Amyotrophic Lateral Sclerosis

Stroke and Vascular Injury

Neuroinflammation Modulation

Therapeutic Development

Peptide Mimetics

Gene Therapy Approaches

Small Molecule Agonists

Combination Strategies

Biomarker and Diagnostic Applications

CSF Biomarkers

Imaging Applications

Aging and Cognitive Decline

Age-Related Changes

Intervention Potential

See Also

See Also

External Links

References

Pathway Diagram

💬 Discussion