ADAR Gene

ADAR Gene

Introduction

The ADAR (Adenosine Deaminase Acting on RNA) gene family encodes sequence-specific RNA editing enzymes that catalyze the hydrolytic deamination of adenosine to inosine (A-to-I editing) in double-stranded RNA (dsRNA). This post-transcriptional modification represents one of the most prevalent forms of RNA editing in mammals, with billions of editing sites identified in the human transcriptome. A-to-I editing fundamentally alters the coding potential and structure of RNA molecules, affecting RNA splicing, miRNA biogenesis, protein translation, and innate immune regulation. The ADAR enzyme family, particularly ADAR1 and ADAR2 (ADARB1), plays critical roles in brain development, synaptic function, and the prevention of aberrant innate immune activation. Dysregulated ADAR activity has been implicated in a growing number of neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). [@samuel2022]

Gene Information

<div class="infobox infobox-gene">
| Property | Value |
|----------|-------|
| Gene Symbol | ADAR |
| Full Name | Adenosine Deaminase Acting On RNA 1 |
| Chromosomal Location | 1q21.3 |
| NCBI Gene ID | 235 |
| OMIM ID | 146920 |
| Ensembl ID | ENSG00000166510 |
| UniProt ID | P55265 |
| Protein Class | RNA editing enzyme / Adenosine deaminase |
| Aliases | ADAR1, ADAR, A-to-I editing enzyme, dsRNA adenosine deaminase |
| Gene Family | ADAR (ADAR1, ADARB1/ADAR2, ADARB2/ADAR3) |
</div>

Protein Structure and Function

ADAR Gene

Introduction

The ADAR (Adenosine Deaminase Acting on RNA) gene family encodes sequence-specific RNA editing enzymes that catalyze the hydrolytic deamination of adenosine to inosine (A-to-I editing) in double-stranded RNA (dsRNA). This post-transcriptional modification represents one of the most prevalent forms of RNA editing in mammals, with billions of editing sites identified in the human transcriptome. A-to-I editing fundamentally alters the coding potential and structure of RNA molecules, affecting RNA splicing, miRNA biogenesis, protein translation, and innate immune regulation. The ADAR enzyme family, particularly ADAR1 and ADAR2 (ADARB1), plays critical roles in brain development, synaptic function, and the prevention of aberrant innate immune activation. Dysregulated ADAR activity has been implicated in a growing number of neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). [@samuel2022]

Gene Information

<div class="infobox infobox-gene">
| Property | Value |
|----------|-------|
| Gene Symbol | ADAR |
| Full Name | Adenosine Deaminase Acting On RNA 1 |
| Chromosomal Location | 1q21.3 |
| NCBI Gene ID | 235 |
| OMIM ID | 146920 |
| Ensembl ID | ENSG00000166510 |
| UniProt ID | P55265 |
| Protein Class | RNA editing enzyme / Adenosine deaminase |
| Aliases | ADAR1, ADAR, A-to-I editing enzyme, dsRNA adenosine deaminase |
| Gene Family | ADAR (ADAR1, ADARB1/ADAR2, ADARB2/ADAR3) |
</div>

Protein Structure and Function

Structure

The ADAR1 protein (~1226 amino acids) contains several critical structural domains:

• N-terminal domain: Contains multiple double-stranded RNA binding motifs (dsRBMs, also called Z-DNA binding domains) that facilitate binding to dsRNA substrates
• Deaminase domain: The C-terminal catalytic domain contains the zinc-coordinating motif (HXE) characteristic of adenosine deaminases
• Zα domain: A Z-DNA binding domain that may play roles in editing regulation

• ADAR1 p150: Interferon-inducible, predominantly localized in the cytoplasm
• ADAR1 p110: Constitutively expressed, primarily nuclear

Catalytic Mechanism

A-to-I editing proceeds through a hydrolytic deamination reaction:

• ADAR recognizes structured dsRNA regions containing adenosine residues
• The catalytic zinc ion (coordinated by HXEXC motifs) activates a water molecule
• The activated water attacks the C6 position of the adenosine base
• The result is conversion of adenosine to inosine, which base-pairs with uridine

• Coding sequences (codon recoding)
• Splice site selection
• miRNA target sites
• RNA secondary structures

Function

ADAR1 performs several essential cellular functions:

Expression Pattern

ADAR is widely expressed throughout the brain with region-specific patterns:

• Cerebral cortex: High expression in layer 2/3 pyramidal neurons, with moderate expression in deeper layers
• Hippocampus: Particularly enriched in CA1 pyramidal neurons and dentate gyrus granule cells
• Cerebellum: High expression in Purkinje cells
• Basal ganglia: Moderate expression in striatal medium spiny neurons and [dopaminergic neurons](/cell-types/dopaminergic-neurons)
• Brainstem: Expression in cranial nerve nuclei

• Neurons: High ADAR1 and ADAR2 expression
• Astrocytes: Moderate expression
• Microglia: Lower expression, increases in response to inflammation

Role in Neurodegeneration

Alzheimer's Disease

A-to-I RNA editing is significantly altered in AD brain tissue, with multiple pathways affected:

[@friedman2019] demonstrated widespread RNA editing alterations in the frontal cortex of AD patients, affecting synaptic proteins, ion channels, and metabolic enzymes.

Amyotrophic Lateral Sclerosis (ALS)

RNA editing abnormalities are increasingly recognized as central to ALS pathogenesis:

[@yamashita2019] characterized RNA editing alterations across multiple ALS models and patient tissues, identifying common pathways affected.

Parkinson's Disease

Other Neurological Disorders

• Aicardi-Goutières Syndrome (AGS): ADAR1 mutations cause constitutive interferon responses due to loss of self-dsRNA editing, leading to early-onset encephalopathy
• Dyschromatosia symmetrica hereditaria: ADAR1 mutations cause pigmentary skin disorders with neurological involvement
• Huntington's disease: Altered RNA editing patterns, particularly in glutamate receptor transcripts
• Epilepsy: ADAR2 activity is modified in epileptic tissue, affecting excitability

Signaling Pathways

Key Downstream Effects

Interactions

Direct Protein Interactions

• ADARB1 (ADAR2): Functional partnership in editing complexes
• DAZAP1: RNA-binding protein involved in editing regulation
• PABPN1: Poly(A) binding protein affecting RNA processing
• hnRNPs: Various hnRNP proteins in RNA metabolism

Pathway Membership

• RNA editing pathway
• Innate immune response (MDA5/IFIH1 signaling)
• AMPA receptor signaling
• miRNA biogenesis pathway
• Type I interferon response

Therapeutic Implications

Therapeutic Strategies

Challenges

• Delivery across the blood-brain barrier
• Specificity for particular brain regions or cell types
• Balancing the dual roles of ADAR in both editing and immune regulation
• Timing of intervention in disease progression

Animal Models

• Adar1 knockout mice: Embryonic lethal due to interferon response to unedited self-dsRNA
• Adar2 knockout mice: Die shortly after birth with severe seizures; GRIA2 editing is essential
• Conditional knockouts: Brain-specific deletions reveal roles in synaptic function
• ALS models: ADAR2 activity modulation affects disease progression

Mechanism Map

See Also

• [GRIA2 Gene](/genes/gria2) - Key ADAR editing target
• [ADARB1 Gene](/genes/adarb1) - ADAR2 enzyme
• [RNA Metabolism in Neurodegeneration](/mechanisms/rna-metabolism-dysregulation)
• [AMPA Receptor Signaling](/mechanisms/ampa-receptor-signaling)
• [Excitotoxicity in Neurodegeneration](/mechanisms/excitotoxicity)
• [Innate Immune Response in Neurodegeneration](/mechanisms/neuroinflammation)
• [Alzheimer's Disease - Molecular Mechanisms](/diseases/alzheimers-disease)
• [ALS - Molecular Mechanisms](/diseases/amyotrophic-lateral-sclerosis)

External Links

• [NCBI Gene: ADAR](https://www.ncbi.nlm.nih.gov/gene/235)
• [UniProt: P55265](https://www.uniprot.org/uniprot/P55265)
• [OMIM: 146920](https://www.omim.org/entry/146920)
• [Ensembl: ENSG00000166510](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000166510)

References