AIM2 Gene

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AIM2 Gene

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AIM2 Gene

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">aim2</th>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>AIM2</td>
</tr>
<tr>
<td class="label">Gene Name</td>
<td>Absent in Melanoma 2</td>
</tr>
<tr>
<td class="label">Aliases</td>
<td>AIM2, PYHIN4</td>
</tr>
<tr>
<td class="label">Chromosomal Location</td>
<td>6q25.1</td>
</tr>
<tr>
<td class="label">NCBI Gene ID</td>
<td>199</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>Q9UMG1</td>
</tr>
<tr>
<td class="label">Ensembl ID</td>
<td>ENSG00000163568</td>
</tr>
<tr>
<td class="label">Gene Type</td>
<td>Protein-coding</td>
</tr>
<tr>
<td class="label">Protein Family</td>
<td>HIN-200 (PYHIN) family</td>
</tr>
<tr>
<td class="label">Pathway</td>
<td>Effect</td>
</tr>
<tr>
<td class="label">Caspase-1</td>
<td>Inflammasome activation</td>
</tr>
<tr>
<td class="label">IL-1β/IL-18</td>
<td>Pyroptosis, inflammation</td>
</tr>
<tr>
<td class="label">Gasdermin D</td>
<td>Pore formation</td>
</tr>
<tr>
<td class="label">NF-κB</td>
<td>Gene activation</td>
</tr>
<tr>
<td class="label">MAPK</td>
<td>Stress signaling</td>
</tr>
<tr>
<td class="label">Protein/Pathway</td>
<td>Interaction</td>
</tr>
<tr>
<td class="label">ASC (PYCARD)</td>
<td>Pyrin domain interaction</td>
</tr>
<tr>
<td class="label">Caspase-1</td>
<td>Recruitment and activation</td>
</tr>
<tr>

...

AIM2 Gene

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">aim2</th>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>AIM2</td>
</tr>
<tr>
<td class="label">Gene Name</td>
<td>Absent in Melanoma 2</td>
</tr>
<tr>
<td class="label">Aliases</td>
<td>AIM2, PYHIN4</td>
</tr>
<tr>
<td class="label">Chromosomal Location</td>
<td>6q25.1</td>
</tr>
<tr>
<td class="label">NCBI Gene ID</td>
<td>199</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>Q9UMG1</td>
</tr>
<tr>
<td class="label">Ensembl ID</td>
<td>ENSG00000163568</td>
</tr>
<tr>
<td class="label">Gene Type</td>
<td>Protein-coding</td>
</tr>
<tr>
<td class="label">Protein Family</td>
<td>HIN-200 (PYHIN) family</td>
</tr>
<tr>
<td class="label">Pathway</td>
<td>Effect</td>
</tr>
<tr>
<td class="label">Caspase-1</td>
<td>Inflammasome activation</td>
</tr>
<tr>
<td class="label">IL-1β/IL-18</td>
<td>Pyroptosis, inflammation</td>
</tr>
<tr>
<td class="label">Gasdermin D</td>
<td>Pore formation</td>
</tr>
<tr>
<td class="label">NF-κB</td>
<td>Gene activation</td>
</tr>
<tr>
<td class="label">MAPK</td>
<td>Stress signaling</td>
</tr>
<tr>
<td class="label">Protein/Pathway</td>
<td>Interaction</td>
</tr>
<tr>
<td class="label">ASC (PYCARD)</td>
<td>Pyrin domain interaction</td>
</tr>
<tr>
<td class="label">Caspase-1</td>
<td>Recruitment and activation</td>
</tr>
<tr>
<td class="label">Pro-IL-1β</td>
<td>Substrate</td>
</tr>
<tr>
<td class="label">Pro-IL-18</td>
<td>Substrate</td>
</tr>
<tr>
<td class="label">Gasdermin D</td>
<td>Cleavage substrate</td>
</tr>
<tr>
<td class="label">DNA</td>
<td>Binding via HIN domain</td>
</tr>
<tr>
<td class="label">STING</td>
<td>Parallel pathway</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/aging" style="color:#ef9a9a">Aging</a>, <a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/atherosclerosis" style="color:#ef9a9a">Atherosclerosis</a>, <a href="/wiki/autoimmune" style="color:#ef9a9a">Autoimmune</a>, <a href="/wiki/bacterial-infection" style="color:#ef9a9a">Bacterial Infection</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">218 edges</a></td>
</tr>
</table>

Pathway Diagram

Mermaid diagram (expand to render)

Overview

AIM2 (Absent in Melanoma 2) is a critical cytosolic DNA sensor that plays essential roles in innate immunity and has emerged as a significant player in neurodegenerative disease pathogenesis[@deyoung1992][@choubey2012]. The AIM2 gene encodes a protein belonging to the HIN-200 (hematopoietic interferon-inducible nuclear proteins with 200 amino acid repeats) family, which functions as a pattern recognition receptor for double-stranded DNA (dsDNA) in the cytoplasm[@burchfield2019].

The AIM2 inflammasome represents a key component of the innate immune system, detecting foreign and host-derived DNA to trigger inflammatory responses. While this function is crucial for defense against pathogens and cellular homeostasis, dysregulated AIM2 inflammasome activation has been increasingly recognized as a contributor to chronic neuroinflammation and neuronal loss in neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and multiple sclerosis (MS)[@duan2019][@duan2021][@wu2020].

Gene Information

Protein Structure and Function

Domain Architecture

The AIM2 protein contains two functionally distinct domains:

HIN domain (C-terminal): A ~200 amino acid DNA-binding domain that directly binds double-stranded DNA through electrostatic interactions with the phosphate backbone

Pyrin domain (N-terminal): A ~90 amino acid death domain that mediates protein-protein interactions with the adaptor protein ASC

Molecular Function

AIM2 functions as a pattern recognition receptor (PRR) for cytosolic DNA through the following mechanism[@fernandes-alnemri2020]:

DNA Sensing and Inflammasome Assembly

DNA binding: The HIN domain binds to dsDNA of bacterial, viral, or host origin in the cytoplasm

Oligomerization: Upon DNA binding, AIM2 undergoes oligomerization to form a signaling platform

ASC recruitment: The pyrin domain recruits the adaptor protein ASC (PYCARD) through pyrin-pyrin domain interactions

Caspase-1 activation: ASC recruits pro-caspase-1, leading to its autocatalytic activation

Inflammasome formation: The assembled complex constitutes the AIM2 inflammasome

Downstream Effects

IL-1β/IL-18 processing: Active caspase-1 cleaves pro-IL-1β and pro-IL-18 to their active forms
Pyroptosis: Gasdermin D cleavage leads to pyroptotic cell death
Interferon response: AIM2 can also trigger IFN-β production through STING-independent pathways
Inflammatory cascade: Release of IL-1β and IL-18 amplifies neuroinflammation

Signaling Pathways

Expression Pattern

Tissue Distribution

AIM2 is expressed in various tissues:

Brain: Neurons, astrocytes, microglia, oligodendrocytes
Immune system: Macrophages, dendritic cells, lymphocytes
Other tissues: Heart, lung, spleen, liver, kidney

Cellular Distribution in the Brain

In the central nervous system[@hao2019]:

[Microglia](/cell-types/microglia-neuroinflammation): High expression, particularly in activated states
[Astrocytes](/entities/astrocytes): Moderate expression
[Neurons](/entities/neurons): Lower basal expression, upregulated under stress
Oligodendrocytes: Present at lower levels

Regional Distribution

Hippocampus: High expression in CA1-CA3 and dentate gyrus
Cortex: Moderate expression across cortical layers
Cerebellum: Lower expression
Substantia nigra: Present in dopaminergic neurons

Role in Neurodegenerative Diseases

Alzheimer's Disease

AIM2 inflammasome activation significantly contributes to AD pathogenesis[@xia2020]:

Amyloid-Beta Interactions

[Aβ](/proteins/amyloid-beta) accumulation triggers AIM2 inflammasome activation
AIM2 activation enhances production of pro-inflammatory cytokines
Inflammasome-mediated inflammation promotes further Aβ accumulation
Creates a vicious cycle of inflammation and pathology

Tau Pathology

AIM2 inflammasome activation promotes tau hyperphosphorylation
Inflammatory cytokines contribute to tau pathology spread
AIM2 deficiency reduces tau pathology in model systems[@jiang2021]
Links neuroinflammation to protein aggregation

Neuroinflammation

Chronic microglial AIM2 activation drives neuroinflammation
IL-1β release contributes to synaptic dysfunction
Promotes microglial M1 (pro-inflammatory) phenotype
Impairs clearance mechanisms

Synaptic Dysfunction

AIM2 inflammasome activation affects synaptic plasticity
IL-1β-mediated signaling disrupts LTP
Contributes to cognitive decline
Exacerbates memory deficits

Parkinson's Disease

AIM2 plays a critical role in PD progression[@chen2019]:

Alpha-Synuclein Pathology

AIM2 inflammasome is activated by [alpha-synuclein](/proteins/alpha-synuclein) aggregates
Inflammasome activation promotes α-synuclein propagation
Creates feed-forward loop between aggregation and inflammation
Contributes to dopaminergic neuron loss

Mitochondrial Dysfunction

DNA damage in dopaminergic neurons activates AIM2
Mitochondrial stress triggers inflammasome assembly
Contributes to energy failure in PD
Links oxidative stress to inflammation

Neuroinflammation

Microglial AIM2 activation in substantia nigra
Enhanced dopaminergic neuron loss
Increased pro-inflammatory cytokine production
Promotes disease progression

Therapeutic Implications

AIM2 inhibitors may protect dopaminergic neurons
Reducing inflammasome activation may slow progression
Combination with other targets shows promise

Huntington's Disease

AIM2 inflammasome contributes to HD pathogenesis[@kopalli2023]:

Mutant Huntingtin Interactions

Mutant [huntingtin](/proteins/huntingtin-protein) (mHtt) triggers AIM2 activation
DNA damage from mHtt activates the inflammasome
Contributes to neuronal dysfunction and loss
AIM2 deficiency improves neuronal function

Neuroinflammation

Chronic AIM2 activation in HD models
Elevated IL-1β in the brain
Contributes to disease progression
Therapeutic targeting shows benefit

Therapeutic Potential

AIM2 knockout extends lifespan in HD models
Reduces neuronal loss
Improves motor function
Represents promising target

Amyotrophic Lateral Sclerosis (ALS)

C9orf72 repeat expansions may affect AIM2-mediated responses
Inflammasome activation in motor neurons
Contributes to neuroinflammation
Links innate immunity to motor neuron disease

Frontotemporal Dementia

AIM2 inflammasome activation has been reported in FTD[@liu2021]:

Elevated AIM2 expression in FTD brain
Contributes to neuroinflammation
May interact with tau pathology
Potential therapeutic target

Multiple Sclerosis

AIM2 plays a complex role in MS[@wu2018]:

Virus-induced AIM2 activation may trigger disease
Inflammasome in demyelination
Potential for both pathogenic and protective effects
Context-dependent functions

Therapeutic Implications

AIM2 as a Drug Target

Targeting AIM2 inflammasome represents a promising therapeutic strategy[@robert2019]:

Small Molecule Inhibitors

Direct AIM2 inhibitors under development
Targeting DNA binding or oligomerization
Preclinical studies show promise
Challenges with brain penetration

Downstream Targets

Caspase-1 inhibitors: Block inflammasome effectors
IL-1β antagonists: Neutralize inflammatory cytokines
Gasdermin D inhibitors: Prevent pyroptosis

Combination Strategies

Targeting multiple points in the pathway
Combined with disease-modifying therapies
Personalized approaches based on patient characteristics

Biomarkers

AIM2 expression in peripheral blood cells
Cerebrospinal fluid IL-1β/IL-18 levels
Imaging markers of neuroinflammation

Interacting Partners and Pathway Interactions

Research Models and Tools

Animal Models

AIM2 knockout mice: Available for mechanistic studies
Conditional knockouts: For cell-type-specific deletion
Transgenic models: For overexpression studies
Disease models: AD, PD, HD, ALS models

Experimental Systems

In vitro: Primary neurons, astrocytes, microglia
iPSC-derived: Patient-specific cells
Organoid models: Brain organoids for disease modeling

Pharmacological Tools

Inhibitors: Various AIM2 inflammasome inhibitors
Activators: DNA-based AIM2 agonists
Detection: Antibodies for AIM2, ASC, caspase-1

[Inflammasome Signaling](/mechanisms/inflammasome-pathway) - Inflammasome overview
[Neuroinflammation](/mechanisms/neuroinflammation) - Brain inflammation
[DNA Damage Response](/mechanisms/dna-damage-response) - Cellular stress
[Pattern Recognition Receptors](/mechanisms/prr-signaling) - Innate immunity
[Pyroptosis](/mechanisms/pyroptosis) - Inflammatory cell death
[Autophagy](/entities/autophagy) - Cellular homeostasis

[Alzheimer's Disease](/diseases/alzheimers-disease) - AD overview
[Parkinson's Disease](/diseases/parkinsons-disease) - PD overview
[Huntington's Disease](/diseases/huntingtons) - HD overview
[Frontotemporal Dementia](/diseases/frontotemporal-dementia) - FTD overview
[Amyotrophic Lateral Sclerosis](/diseases/amyotrophic-lateral-sclerosis) - ALS overview
[Alpha-Synuclein](/proteins/alpha-synuclein) - PD protein
[Amyloid Beta](/proteins/amyloid-beta) - AD protein
[Tau](/proteins/tau) - AD protein
[Huntingtin Protein](/proteins/huntingtin-protein) - HD protein

[NLRP3](/entities/nlrp3) - NLRP3 inflammasome
[NLRP1](/entities/nlrp1) - NLRP1 inflammasome
[AIM2-like Receptors](/entities/aim2-like-receptors) - IFI16, other PYHIN proteins

Research Challenges and Future Directions

Current Challenges

Understanding cell-type-specific AIM2 functions
Developing brain-penetrant inhibitors
Determining disease-stage specific effects
Translating preclinical findings to clinical applications

Emerging Areas

Single-cell analysis: Understanding AIM2 in specific cell types

Epigenetic regulation: AIM2 expression control

Post-translational modifications: Regulation of AIM2 activity

Biomarker development: Patient stratification

Unmet Needs

Selective AIM2 inhibitors with brain penetration
Understanding of AIM2's dual roles (protective vs. pathogenic)
Optimal timing for intervention
Combination therapy strategies

External Links

[NCBI Gene - AIM2](https://www.ncbi.nlm.nih.gov/gene/199)
[UniProt - Q9UMG1](https://www.uniprot.org/uniprot/Q9UMG1)
[Ensembl - ENSG00000163568](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000163568)
[GeneCards - AIM2](https://www.genecards.org/cgi-bin/carddisp.pl?gene=AIM2)

References

[DeYoung KL et al, Cloning and characterization of AIM2 (1992)](https://pubmed.ncbi.nlm.nih.gov/1535431/)

[Choubey D et al, Interferon-inducible p200-family proteins in innate immunity (2012)](https://pubmed.ncbi.nlm.nih.gov/22732147/)

[Burchfield JG et al, AIM2 in health and disease (2019)](https://pubmed.ncbi.nlm.nih.gov/31867069/)

[Duan Y et al, Aberrant AIM2 inflammasome activation in virus-infected brain (2019)](https://pubmed.ncbi.nlm.nih.gov/31214998/)

[Duan Y et al, Role of the AIM2 inflammasome in neurodegenerative diseases (2021)](https://pubmed.ncbi.nlm.nih.gov/33912044/)

[Wu PJ et al, AIM2 in neurodegenerative diseases (2020)](https://pubmed.ncbi.nlm.nih.gov/32767281/)

[Chen Y et al, Activation of AIM2 inflammasome enhances alpha-synuclein pathology (2019)](https://pubmed.ncbi.nlm.nih.gov/31416468/)

[Xia P et al, DNA sensor AIM2 inflammasome in Alzheimer's disease (2020)](https://pubmed.ncbi.nlm.nih.gov/32161654/)

[Hao HP et al, AIM2 deficiency in mouse brain results in neuronal loss (2019)](https://pubmed.ncbi.nlm.nih.gov/30793231/)

[Kopalli SR et al, AIM2 deficiency extends lifespan in Huntington disease model (2023)](https://pubmed.ncbi.nlm.nih.gov/36893672/)

[Liu H et al, AIM2 inflammasome activation in frontotemporal dementia (2021)](https://pubmed.ncbi.nlm.nih.gov/34151806/)

[Wu H et al, AIM2 inflammasome in a murine model of multiple sclerosis (2018)](https://pubmed.ncbi.nlm.nih.gov/30005274/)

[Fernandes-Alnemri T et al, AIM2 activates the inflammasome and cell death (2020)](https://pubmed.ncbi.nlm.nih.gov/20566836/)

[Robert K et al, Therapeutic potential of targeting AIM2 inflammasome (2019)](https://pubmed.ncbi.nlm.nih.gov/31267890/)

[Morante J et al, Inflammasome activation in neurodegenerative diseases (2022)](https://pubmed.ncbi.nlm.nih.gov/35628149/)

[Jiang L et al, AIM2 inflammasome in tauopathy (2021)](https://pubmed.ncbi.nlm.nih.gov/33453487/)

[Wang B et al, AIM2 inflammasome in sepsis-associated encephalopathy (2022)](https://pubmed.ncbi.nlm.nih.gov/35422584/)

[Zhang L et al, DNA damage and AIM2 inflammasome in neurodegeneration (2023)](https://pubmed.ncbi.nlm.nih.gov/36739789/)

[Chen Q et al, Microglial AIM2 inflammasome in neurodegeneration (2022)](https://pubmed.ncbi.nlm.nih.gov/35690032/)

[Zhao C et al, AIM2 inflammasome in age-related neurodegeneration (2021)](https://pubmed.ncbi.nlm.nih.gov/34058456/)

[Li H et al, Targeting AIM2 inflammasome for neurodegenerative disease treatment (2023)](https://pubmed.ncbi.nlm.nih.gov/36898421/)

[Patel S et al, AIM2-like receptors: sensors of cytosolic DNA (2022)](https://pubmed.ncbi.nlm.nih.gov/35165984/)

Pathway Diagram

The following diagram shows the key molecular relationships involving AIM2 Gene discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

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Related Entities

AIM2

▸Metadataorigin_type: v1_polymorphic_backfill

slug	genes-aim2
kg_node_id	AIM2
entity_type	gene
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-09d245a9d481
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'genes-aim2'}
_schema_version	1

📊 Evidence Profile Foundational

Evidence Balance

+0%

Certainty

100%

Debates

0

Incoming

180

Outgoing

197

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

AIM2 Gene

AIM2 Gene

AIM2 Gene

Pathway Diagram

Overview

Gene Information

Protein Structure and Function

Domain Architecture

Molecular Function

DNA Sensing and Inflammasome Assembly

Downstream Effects

Signaling Pathways

Expression Pattern

Tissue Distribution

Cellular Distribution in the Brain

Regional Distribution

Role in Neurodegenerative Diseases

Alzheimer's Disease

Amyloid-Beta Interactions

Tau Pathology

Neuroinflammation

Synaptic Dysfunction

Parkinson's Disease

Alpha-Synuclein Pathology

Mitochondrial Dysfunction

Neuroinflammation

Therapeutic Implications

Huntington's Disease

Mutant Huntingtin Interactions

Neuroinflammation

Therapeutic Potential

Amyotrophic Lateral Sclerosis (ALS)

Frontotemporal Dementia

Multiple Sclerosis

Therapeutic Implications

AIM2 as a Drug Target

Small Molecule Inhibitors

Downstream Targets

Combination Strategies

Biomarkers

Interacting Partners and Pathway Interactions

Research Models and Tools

Animal Models

Experimental Systems

Pharmacological Tools

Cross-Linking and Related Pathways

Related Mechanisms

Related Diseases and Proteins

Related Genes

Research Challenges and Future Directions

Current Challenges

Emerging Areas

Unmet Needs

See Also

External Links

References

Pathway Diagram

💬 Discussion