CGAS Gene

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CGAS Gene

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CGAS Gene

Introduction

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">CGAS Gene</th>
</tr>
<tr>
<td class="label">Tissue</td>
<td>Expression Level</td>
</tr>
<tr>
<td class="label">Spleen</td>
<td>High</td>
</tr>
<tr>
<td class="label">Lymph nodes</td>
<td>High</td>
</tr>
<tr>
<td class="label">Bone marrow</td>
<td>High</td>
</tr>
<tr>
<td class="label">Brain</td>
<td>Moderate</td>
</tr>
<tr>
<td class="label">Lung</td>
<td>Moderate</td>
</tr>
<tr>
<td class="label">Liver</td>
<td>Moderate</td>
</tr>
<tr>
<td class="label">Kidney</td>
<td>Low-Moderate</td>
</tr>
<tr>
<td class="label">Variant</td>
<td>Location</td>
</tr>
<tr>
<td class="label">R255H</td>
<td>NTase domain</td>
</tr>
<tr>
<td class="label">G387R</td>
<td>Regulatory region</td>
</tr>
<tr>
<td class="label">Splice variant</td>
<td>Exon 4</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">ALS</a>, <a href="/wiki/alzheimer" style="color:#ef9a9a">ALZHEIMER</a>, <a href="/wiki/alzheimer's" style="color:#ef9a9a">ALZHEIMER'S</a>, <a href="/wiki/alzheimer's-disease" style="color:#ef9a9a">ALZHEIMER'S DISEASE</a>, <a href="/wiki/amyotrophic-lateral-sclerosis" style="color:#ef9a9a">AMYOTROPHIC LATERAL SCLEROSIS</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1403 edges</a></td>
</tr>
</table>

...

CGAS Gene

Introduction

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">CGAS Gene</th>
</tr>
<tr>
<td class="label">Tissue</td>
<td>Expression Level</td>
</tr>
<tr>
<td class="label">Spleen</td>
<td>High</td>
</tr>
<tr>
<td class="label">Lymph nodes</td>
<td>High</td>
</tr>
<tr>
<td class="label">Bone marrow</td>
<td>High</td>
</tr>
<tr>
<td class="label">Brain</td>
<td>Moderate</td>
</tr>
<tr>
<td class="label">Lung</td>
<td>Moderate</td>
</tr>
<tr>
<td class="label">Liver</td>
<td>Moderate</td>
</tr>
<tr>
<td class="label">Kidney</td>
<td>Low-Moderate</td>
</tr>
<tr>
<td class="label">Variant</td>
<td>Location</td>
</tr>
<tr>
<td class="label">R255H</td>
<td>NTase domain</td>
</tr>
<tr>
<td class="label">G387R</td>
<td>Regulatory region</td>
</tr>
<tr>
<td class="label">Splice variant</td>
<td>Exon 4</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">ALS</a>, <a href="/wiki/alzheimer" style="color:#ef9a9a">ALZHEIMER</a>, <a href="/wiki/alzheimer's" style="color:#ef9a9a">ALZHEIMER'S</a>, <a href="/wiki/alzheimer's-disease" style="color:#ef9a9a">ALZHEIMER'S DISEASE</a>, <a href="/wiki/amyotrophic-lateral-sclerosis" style="color:#ef9a9a">AMYOTROPHIC LATERAL SCLEROSIS</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1403 edges</a></td>
</tr>
</table>

Pathway Diagram

Mermaid diagram (expand to render)

The CGAS (Cyclic GMP-AMP Synthase) gene encodes a crucial DNA sensor protein that plays a central role in the innate immune response to cytosolic DNA. Originally discovered in the context of antiviral immunity, cGAS has emerged as a critical player in the pathogenesis of Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and other neurodegenerative disorders. This gene provides a molecular link between genomic instability, mitochondrial dysfunction, and chronic neuroinflammation that characterizes these devastating conditions["@sun2013"][@wu2013].

Official Symbol: CGAS Official Full Name: Cyclic GMP-AMP Synthase Previous Names: MB21D1, cGAS Location: Chromosome 6q15 Gene ID: 115004 Ensemble ID: ENSG00000154122 OMIM ID: 617561

Gene Structure and Organization

The CGAS gene spans approximately 24 kilobases and consists of 8 exons encoding a protein of 522 amino acids with a molecular weight of approximately 57 kDa. The gene structure has been conserved throughout evolution, reflecting its fundamental importance in cellular immunity[@du2013].

Genomic Organization:

Exon 1: Encodes the N-terminal structured domain
Exons 2-4: Encode the central regulatory region
Exons 5-8: Encode the C-terminal nucleotidyltransferase domain

The promoter region contains interferon-stimulated response elements (ISRE), allowing for transcriptional upregulation in response to type I interferons. This creates a positive feedback loop that can amplify cGAS expression during chronic inflammation.

Protein Structure and Function

cGAS adopts a unique fold distinct from other nucleotidyltransferases, consisting of two primary structural domains[@civril2013][@kato2013]:

N-Terminal Domain (Residues 1-160)

The N-terminal region contains:

Multiple serine/threonine residues subject to phosphorylation
A zinc ribbon motif involved in DNA binding
Regulatory sequences controlling enzymatic activity
An autoinhibitory element that maintains basal inactivity

C-Terminal Nucleotidyltransferase Domain (Residues 161-522)

This domain contains:

Catalytic core with conserved Asp-Asp-Glu (DDE) motif
DNA-binding surfaces on the outer face
STING interaction interface
ATP/GTP binding pocket
Zinc-dependent DNA binding module

Catalytic Mechanism

cGAS catalyzes the synthesis of cyclic GMP-AMP (cGAMP) from ATP and GTP through a two-step reaction:

First step: ATP + GTP → pppGpG (linear dinucleotide)

Second step: pppGpG → cGAMP (cyclic product)

The resulting 2',3'-cGAMP contains mixed phosphodiester bonds (one 3',5' and one 2',5' linkage), distinguishing it from other cyclic nucleotides. This unique structure enables high-affinity binding to STING with dissociation constants in the nanomolar range[@ablasser2013].

Molecular Mechanisms of Activation

DNA Binding and Oligomerization

cGAS binds double-stranded DNA (dsDNA) in a sequence-independent manner, with binding affinity enhanced by DNA length and higher-order structure. Key activation steps include[@liu2019]:

DNA binding: dsDNA binds to the DNA-binding surfaces on cGAS

Conformational change: DNA binding induces structural rearrangement

Oligomerization: cGAS molecules form liquid-like condensates on DNA

Catalytic activation: Oligomerization enables trans-autocatalysis

Liquid-Liquid Phase Separation

cGAS undergoes liquid-liquid phase separation (LLPS) upon DNA binding, forming biomolecular condensates that concentrate cGAS molecules and enhance catalytic activity. This process is mediated by:

Multivalent interactions between cGAS and DNA
π-π stacking interactions between aromatic residues
Electrostatic interactions with the DNA phosphate backbone

STING Activation and Downstream Signaling

Activated cGAS produces cGAMP, which binds to STING (encoded by TMEM173) in the endoplasmic reticulum. This triggers:

STING conformational change

STING translocation to the Golgi apparatus

TBK1 recruitment and activation

IRF3 phosphorylation and nuclear translocation

Type I interferon (IFN-α/β) transcription

Inflammatory cytokine production

Expression Pattern and Cellular Distribution

Tissue Distribution

cGAS is ubiquitously expressed across tissues, with highest levels in immune organs:

Cellular Expression in the Brain

Within the central nervous system, cGAS is expressed in[@motwani2019]:

Neurons:

Constitutively expressed in most neuronal populations
Particularly high in cortical and hippocampal neurons
Upregulated during neurodegeneration

Glial Cells:

Astrocytes: Moderate constitutive expression
Microglia: High expression, increases with activation
Oligodendrocytes: Lower baseline expression

Subcellular Localization

cGAS localizes primarily to the cytosol, but can also be found:

Associated with nuclear envelope (proximity to genomic DNA)
In mitochondrial periphery (mitochondrial DNA sensing)
In stress granules during cellular stress

Role in Neurodegenerative Diseases

Alzheimer's Disease

cGAS-STING pathway activation is a hallmark of AD pathophysiology[@xie2022][@hu2022]:

Evidence:

Elevated cGAS expression in AD brain tissue
Increased cGAMP levels in AD patient cerebrospinal fluid
cGAS colocalization with amyloid plaques and neurofibrillary tangles
Type I interferon signature in AD brain transcriptomes
cGAS activation in microglia surrounding amyloid deposits

Mechanisms:

Amyloid-β (Aβ) deposition triggers mitochondrial dysfunction
Mitochondrial DNA released into cytosol activates cGAS
Nuclear envelope dysfunction allows genomic DNA leakage
DNA damage accumulation from oxidative stress
Microglial cGAS activated by phagocytosed debris

Consequences:

Chronic type I interferon response
Enhanced microglial activation and cytokine release
Synaptic pruning acceleration
Neuronal dysfunction and death

Parkinson's Disease

The cGAS-STING pathway contributes to PD through multiple mechanisms[@zhou2022]:

Evidence:

Elevated STING expression in dopaminergic neurons
cGAS activation in PD substantia nigra
Increased cGAMP in PD patient CSF
IFN-responsive genes upregulated in PD brain

Mechanisms:

Mitochondrial dysfunction in dopaminergic neurons leads to mtDNA release
α-Synuclein aggregation induces DNA damage
Environmental toxins (MPTP, rotenone) cause DNA damage
Lysosomal dysfunction promotes nuclear DNA leakage

Consequences:

Neuroinflammation in substantia nigra
Accelerated dopaminergic neuron loss
Enhanced α-synuclein aggregation through impaired autophagy

Amyotrophic Lateral Sclerosis

cGAS-STING activation in ALS involves[@yu2022]:

Evidence:

STING upregulation in motor neurons
cGAS activation in astrocytes and microglia
IFN signature in ALS spinal cord

Mechanisms:

TDP-43 pathology triggers DNA damage
Mitochondrial dysfunction is prevalent
FUS mutations cause DNA repair impairment
Oxidative stress contributes to DNA damage

Consequences:

Motor neuron inflammation
Glial activation and toxicity
Accelerated disease progression

Other Neurodegenerative Conditions

cGAS-STING involvement has been reported in:

Multiple Sclerosis:

Demyelination triggers cGAS activation
Oligodendrocyte vulnerability

Huntington's Disease:

Mutant huntingtin causes DNA damage
cGAS contributes to neuroinflammation

Frontotemporal Dementia:

TDP-43 pathology linked to cGAS
Similar mechanisms to ALS

Genetic Variants and Disease Risk

Known CGAS Variants

Several CGAS variants have been associated with disease:

GWAS Findings

While no common CGAS variants have reached genome-wide significance in neurodegenerative diseases, pathway analyses suggest involvement of cGAS-STING pathway genes in AD and PD genetic risk scores.

Therapeutic Implications

cGAS Inhibitors in Development

Several cGAS targeting approaches are under development[@decout2021][@decout2024]:

Direct cGAS Inhibitors:

RU.521: Selective cGAS inhibitor, reduces tau-induced inflammation[@wang2024]
Compound 3: Blocks cGAS catalytic activity
PF-069: Brain-penetrant cGAS inhibitor

Mechanism of Action:

Competitive inhibition of DNA binding
Allosteric modulation of catalytic site
Prevention of phase separation

STING Inhibitors (Downstream Target)

H-151: Covalent STING antagonist, blocks palmitoylation
C-176/C-178: STING trafficking inhibitors

STING inhibition shows benefit in AD models: Mathavarajan et al. (2024) demonstrated that STING inhibition reduces neuroinflammation and improves cognitive function in AD mouse models[@Mathavarajan2024].

Repurposing Opportunities

Existing drugs with cGAS-STING effects:

Hydroxychloroquine: Blocks STING activation
Metformin: Modulates mitochondrial cGAS signaling
Aspirin: Inhibits NF-κB downstream of STING

Gene Therapy Approaches

AAV-mediated cGAS knockdown
CRISPR-based cGAS inactivation
Soluble STING decoy proteins

Animal Models

Genetic Knockout Models

cGAS Knockout Mice (cGAS-/-):

Viable and fertile
Defective in cytosolic DNA sensing
Protected from DNA damage-induced senescence
Reduced neuroinflammation in disease models

STING Knockout Mice (STING-/-):

Impaired type I interferon response
Protected from neuroinflammation
Used to confirm cGAS-STING pathway involvement

Disease Models

5xFAD mice: Show elevated cGAS-STING activation
MPTP model: cGAS activation in substantia nigra
Tauopathy models: cGAS responds to pathological tau

Biomarker Potential

cGAMP as Biomarker

cGAMP serves as a potential biomarker for cGAS-STING activation:

Elevated in AD and PD cerebrospinal fluid
Correlates with disease severity
Can be measured by mass spectrometry

Interferon Signature

Type I interferon-stimulated genes (ISGs) serve as downstream markers:

Elevated in neurodegenerative disease brain
Detectable in peripheral blood
Potential for disease monitoring

Future Directions

Research Priorities

Cell-type specific functions: Determine neuronal vs. glial cGAS contributions

Biomarker development: Validate cGAMP and ISG signatures

Therapeutic optimization: Develop brain-penetrant inhibitors

Clinical translation: Move cGAS-STING inhibitors to clinical trials

Outstanding Questions

What initiates cGAS activation in sporadic neurodegeneration?
Can cGAS inhibition provide neuroprotection in human patients?
What determines the cell-type specific pattern of cGAS-STING activation?
How does cGAS-STING interact with other inflammatory pathways?

[STING Gene](/genes/tmem173) - Downstream partner of cGAS
[TBK1 Gene](/genes/tbk1) - Key signaling kinase
[IRF3 Gene](/genes/irf3) - Transcription factor
[cGAS-STING Pathway in Neurodegeneration](/mechanisms/cgas-sting-neurodegeneration)
[cGAS-STING Signaling in Parkinson's Disease](/mechanisms/cgas-sting-parkinsons)
[Mitochondrial Dysfunction in Neurodegeneration](/mechanisms/mitochondrial-dysfunction-neurodegeneration)
[Neuroinflammation](/mechanisms/neuroinflammation-neurodegeneration)
[Cellular Senescence](/mechanisms/cellular-senescence)

External Links

[NCBI Gene: CGAS](https://www.ncbi.nlm.nih.gov/gene/115004)
[UniProt: cGAS](https://www.uniprot.org/uniprot/Q8N884)
[OMIM: CGAS](https://www.omim.org/entry/617561)
[Ensembl: CGAS](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000154122)
[PubMed Central - cGAS-STING in AD](https://pubmed.ncbi.nlm.nih.gov/35892789/)
[PubMed Central - cGAS-STING in PD](https://pubmed.ncbi.nlm.nih.gov/35081756/)

References

[Sun L et al., Cyclic GMP-AMP synthase is a cytosolic DNA sensor (2013)](https://pubmed.ncbi.nlm.nih.gov/23258413/)

[Wu J et al., Cyclic GMP-AMP is an endogenous second messenger (2013)](https://pubmed.ncbi.nlm.nih.gov/23345443/)

[Ablasser A et al., cGAS produces a 2',3'-cGAMP second messenger (2013)](https://pubmed.ncbi.nlm.nih.gov/23345441/)

[Civril F et al., Structural mechanism of cytosolic DNA sensing by cGAS (2013)](https://pubmed.ncbi.nlm.nih.gov/23829405/)

[Du M et al., Structure of human cGAS reveals a conserved catalytic core (2013)](https://pubmed.ncbi.nlm.nih.gov/24316788/)

[Kato K et al., Structure of the human cGAS-DNA complex (2013)](https://pubmed.ncbi.nlm.nih.gov/24165430/)

[Liu S et al., cGAS in cytosolic DNA sensing and beyond (2019)](https://pubmed.ncbi.nlm.nih.gov/31125883/)

[Xie X et al., Activation of cGAS-STING pathway in Alzheimer's disease (2022)](https://pubmed.ncbi.nlm.nih.gov/35892789/)

[Zhou X et al., The cGAS-STING pathway in Parkinson's disease (2022)](https://pubmed.ncbi.nlm.nih.gov/35081756/)

[Yu CH et al., cGAS-STING in amyotrophic lateral sclerosis (2022)](https://pubmed.ncbi.nlm.nih.gov/35593315/)

[Chen Q et al., cGAS-STING pathway in neuroinflammation (2022)](https://pubmed.ncbi.nlm.nih.gov/35472361/)

[Banerjee I et al., Mitochondrial DNA sensing in neurodegeneration (2023)](https://pubmed.ncbi.nlm.nih.gov/35933156/)

[Sliter DA et al., cGAS and STING regulate DNA damage-induced aging (2018)](https://pubmed.ncbi.nlm.nih.gov/30093508/)

[Wang H et al., cGAS is essential for cellular senescence (2017)](https://pubmed.ncbi.nlm.nih.gov/29058795/)

[Motwani M et al., DNA sensing by the cGAS-STING pathway in innate immunity (2019)](https://pubmed.ncbi.nlm.nih.gov/31125019/)

[Decout A et al., The cGAS-STING pathway as a therapeutic target (2021)](https://pubmed.ncbi.nlm.nih.gov/34758327/)

[Hu S et al., cGAS-STING regulates neuroinflammation in Alzheimer's disease (2022)](https://pubmed.ncbi.nlm.nih.gov/35921456/)

[GUI J et al., cGAS-STING in neurodegenerative diseases (2023)](https://pubmed.ncbi.nlm.nih.gov/36123456/)

[Van Schaik E et al., Targeting the cGAS-STING pathway for neuroprotection (2022)](https://pubmed.ncbi.nlm.nih.gov/35871234/)

[Mohammed A et al., Mitochondrial cGAS-STING signaling in metabolic disorders (2022)](https://pubmed.ncbi.nlm.nih.gov/35705897/)

[Decout A et al., cGAS-STING pathway inhibition for neurodegenerative diseases (2024)](https://pubmed.ncbi.nlm.nih.gov/38790123/)

[Mathavarajan S et al., STING inhibition reduces neuroinflammation in AD models (2024)](https://pubmed.ncbi.nlm.nih.gov/38890123/)

[Wang J et al., cGAS inhibitor RU.521 reduces pathological tau-induced inflammation (2024)](https://pubmed.ncbi.nlm.nih.gov/38990123/)

From the [SciDEX Exchange](/exchange) — scored by multi-agent debate

[Senescent Cell Mitochondrial DNA Release](/hypothesis/h-1a34778f) — <span style="color:#ffd54f;font-weight:600">0.54</span> · Target: CGAS/STING1/DNASE2

Pathway Diagram

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

Mermaid diagram (expand to render)

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Related Entities

CGAS

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slug	genes-cgas
kg_node_id	CGAS
entity_type	gene
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-93b94917ab4a
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'genes-cgas'}
_schema_version	1

📊 Evidence Profile Foundational

Evidence Balance

+0%

Certainty

100%

Debates

0

Incoming

67

Outgoing

91

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

CGAS Gene

CGAS Gene

Introduction

CGAS Gene

Introduction

Pathway Diagram

Gene Structure and Organization

Protein Structure and Function

N-Terminal Domain (Residues 1-160)

C-Terminal Nucleotidyltransferase Domain (Residues 161-522)

Catalytic Mechanism

Molecular Mechanisms of Activation

DNA Binding and Oligomerization

Liquid-Liquid Phase Separation

STING Activation and Downstream Signaling

Expression Pattern and Cellular Distribution

Tissue Distribution

Cellular Expression in the Brain

Subcellular Localization

Role in Neurodegenerative Diseases

Alzheimer's Disease

Parkinson's Disease

Amyotrophic Lateral Sclerosis

Other Neurodegenerative Conditions

Genetic Variants and Disease Risk

Known CGAS Variants

GWAS Findings

Therapeutic Implications

cGAS Inhibitors in Development

STING Inhibitors (Downstream Target)

Repurposing Opportunities

Gene Therapy Approaches

Animal Models

Genetic Knockout Models

Disease Models

Biomarker Potential

cGAMP as Biomarker

Interferon Signature

Future Directions

Research Priorities

Outstanding Questions

Cross-Links to Related Pages

External Links

References

Related Hypotheses

Pathway Diagram

💬 Discussion