ADAR2-dependent A-to-I RNA editing in the extracellular linear and circular RNAs

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Amyotrophic lateral sclerosis (ALS) lacks reliable biomarkers.
• Reduced RNA editing at the GluA2 Q/R site in motor neurons is linked to ADAR2 downregulation in sporadic ALS.
• TDP-43 pathology, common in ALS, is found in ADAR2-deficient motor neurons, suggesting ADAR2's role in ALS pathogenesis.

Purpose of the Study:

• To identify novel ADAR2-dependent RNA editing sites.
• To explore the potential of extracellular RNA editing efficiencies as ALS biomarkers.
• To investigate ADAR2 activity in relation to ALS.

Main Methods:

• Searched for ADAR2-dependent sites in mouse motor neurons and human SH-SY5Y cells.
• Analyzed RNA editing efficiencies in host RNAs and circular RNAs.
• Investigated RNAs in cell culture medium to mimic extracellular detection.

Main Results:

• Identified 10 ADAR2-dependent sites in five host RNAs in SH-SY5Y cells and their medium.
• Newly identified the arginine/glycine site of SON mRNA as ADAR2-dependent.
• Detected a circular RNA with an ADAR2-dependent site in cells and medium.

Conclusions:

• Changes in RNA editing efficiencies at identified sites in extracellular RNAs may serve as potential ALS biomarkers.
• ADAR2-dependent RNA editing sites offer a new avenue for ALS biomarker discovery.
• Monitoring extracellular RNA editing could reflect cellular ADAR2 activity and ALS status.