Project information
Roles of Adar1 and Adar2 in Brain Development (RAABD)

ADAR1 (encoded by ADAR gene) and ADAR2 (encoded by ADARB1 gene) proteins play crucial roles in the central nervous system (CNS) by modulating gene expression and protein function. Defects in ADARs activity are implicated in various neurological disorders. ADAR1 is involved in modulating the immune response as it edits dsRNA and thus prevents unedited dsRNA from being recognized as a foreign element by innate immunity, which would otherwise trigger chronic interferon responses and neuroinflammation. Mutations in ADAR are associated with Aicardi-Goutières syndrome 6 (AGS6), a severe encephalopathy characterized by aberrant immune responses. Without ADAR1 activity, neurons accumulate unedited dsRNA, which can lead to cell stress, apoptosis, and chronic inflammation and neurodegeneration.
The role of ADAR2 in CNS is even more profound because it plays a crucial role in the production of ionotropic glutamate AMPA receptors (AMPARs), heterotetrameric receptor proteins that mediate fast excitatory synaptic neurotransmission. AMPARs become aberrantly calcium-permeable if the mRNA transcript (GRIA2) encoding glutamate receptor subunit A2 (GluA2) is not properly edited by ADARs. This crucial editing event occurs at the Q/R site and results in a codon change from glutamine (Q) to arginine (R) thus reducing the receptor's calcium permeability. ADAR2 also edits serotonin receptor (Htr2c) mRNA, altering its function and serotonin signalling. Mutations in ADARB1 can cause severe and fatal drug-resistant infant epilepsy; deficient ADAR2 activity, has also been linked to neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). Precise modulation of RNA sequences ensures proper protein function and protects against aberrant immune activation. Both ADAR proteins are integral in maintaining neuronal homeostasis through their RNA editing activities.