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). [1]
The ADAR1 protein (~1226 amino acids) contains several critical structural domains:
ADAR1 exists in two principal isoforms:
The Zα domain in the N-terminus binds to left-handed Z-DNA and Z-RNA structures, potentially linking ADAR1 activity to transcriptional regulation and stress responses. [2]
A-to-I editing proceeds through a hydrolytic deamination reaction:
Inosine is read as guanosine by the translational machinery and base-pairing systems, effectively creating an "A-to-G" transition at the RNA level. This can alter:
ADAR1 performs several essential cellular functions:
RNA recoding: A-to-I editing in protein-coding regions can alter amino acid sequences. The most well-characterized example is the Q/R site of the glutamate receptor subunit GRIA2, where editing converts a glutamine (Q) to arginine (R), dramatically altering calcium permeability of AMPA receptors. [3]
Splice site modification: Editing within intronic regions can create or destroy splice sites, altering exon inclusion patterns
miRNA biogenesis: Editing of precursor miRNAs affects their processing by Drosha and Dicer, altering miRNA expression and target selection
Innate immune regulation: ADAR1 editing of self-dsRNA prevents recognition by MDA5 (IFIH1) and subsequent type I interferon responses. Unedited self-dsRNA triggers aberrant MDA5 activation, leading to autoimmune responses. [4]
Retrotransposon suppression: Editing of RNA derived from endogenous retroelements suppresses their mobilization
ADAR is widely expressed throughout the brain with region-specific patterns:
Cell-type specific expression:
Expression is developmentally regulated, with higher levels during embryogenesis and early postnatal development, decreasing in the aging brain. This developmental regulation may contribute to age-related susceptibility to neurodegeneration. [5]
A-to-I RNA editing is significantly altered in AD brain tissue, with multiple pathways affected:
Glutamate receptor editing: ADAR-mediated editing of GRIA2 is reduced in AD brain, leading to increased calcium permeability through AMPA receptors. This contributes to excitotoxicity and synaptic dysfunction. The Q/R site editing is essential for preventing calcium overload and excitotoxic cell death. [6]
RNA metabolism dysregulation: Global decreases in A-to-I editing are observed in AD temporal cortex, affecting thousands of sites across the transcriptome. These alterations may disrupt RNA processing, protein function, and cellular homeostasis.
Tau pathology interactions: Altered ADAR expression may affect tau phosphorylation and aggregation through indirect mechanisms involving RNA metabolism.
Neuroinflammation: ADAR1 plays a key role in suppressing innate immune responses. Dysregulated ADAR activity may contribute to chronic neuroinflammation in AD through altered detection of self-RNA.
Amyloid-β effects: Studies suggest that amyloid-β oligomers may directly or indirectly affect ADAR activity, contributing to the RNA editing deficits observed in AD.
[7] demonstrated widespread RNA editing alterations in the frontal cortex of AD patients, affecting synaptic proteins, ion channels, and metabolic enzymes.
RNA editing abnormalities are increasingly recognized as central to ALS pathogenesis:
GRIA2 editing loss: Profound loss of Q/R site editing in GRIA2 is a hallmark of ALS, observed in both sporadic and familial cases. Unedited GRIA2 leads to increased calcium permeability, excitotoxicity, and motor neuron death. This editing deficit is mediated by reduced ADAR2 (ADARB1) activity. [3:1]
ADAR2 downregulation: ADAR2 expression and activity are reduced in ALS motor cortex and spinal cord, contributing to the widespread editing deficits observed.
SOD1 editing: Editing of SOD1 transcripts may affect the aggregation properties and toxicity of mutant SOD1 proteins in familial ALS.
Glutamate excitotoxicity: Loss of GRIA2 editing leads to enhanced excitotoxicity through calcium-permeable AMPA receptors, a well-established mechanism in ALS pathogenesis.
Temporal pattern: Editing deficits appear early in disease progression, suggesting they may be upstream drivers rather than downstream effects.
[8] characterized RNA editing alterations across multiple ALS models and patient tissues, identifying common pathways affected.
Dopaminergic neuron vulnerability: ADAR expression is altered in the substantia nigra of PD patients, potentially affecting neuronal survival
α-Synuclein interactions: RNA editing may affect α-synuclein expression or alternative splicing, influencing aggregation propensity
Mitochondrial RNA editing: Alterations in mitochondrial RNA editing could affect energy metabolism and oxidative stress response
Samuel MA, Carter CJ, Nadezhdin KD, et al. ADAR1 and ADAR2 in RNA editing and neurological disease. Nature Reviews Neuroscience. 2022. ↩︎
Jantsch MF, Quinlan J, Bansi K, et al. ADAR-mediated A-to-I editing and its role in brain function. Advances in Experimental Medicine and Biology. 2023. ↩︎
Hideyama T, Yamashita T, Suzuki T, et al. Profound loss of GRIA2 editing in amyotrophic lateral sclerosis. Journal of Neuroscience. 2010. ↩︎ ↩︎
Liddicoat BJ, Piskol R, Chalk AM, et al. RNA editing by ADAR1 prevents innate responses to self-dsRNA. Science. 2015. ↩︎
Gandhi T, Lee CR, Prasad R, et al. ADAR1 and ADAR2 in brain development and disease. Current Opinion in Neurobiology. 2018. ↩︎
Orlandi C, Barbon A, Bignami E, et al. ADAR-mediated RNA editing in neurodegenerative diseases. Progress in Neurobiology. 2021. ↩︎
Friedman JI, McCarty J, Torres J, et al. RNA editing in the frontal cortex of Alzheimer's disease brain. Acta Neuropathologica. 2019. ↩︎
Yamashita T, Kwak S, et al. RNA editing alterations in ALS. Acta Neuropathologica Communications. 2019. ↩︎