Mapping and Hijacking the ADAR1 Saturation Point: A Bifunctional Strategy

In the C9orf72 hexanucleotide repeat expansion (HRE), the predominant genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD), the formation of complex RNA secondary structures presents an unprecedented burden of endogenous double-stranded RNA (dsRNA). The adenosine deaminase ADAR1 is the guardian of this dsRNA landscape, converting adenosine-to-inosine (A-to-I) to prevent recognition by the cytoplasmic innate immune sensor MDA5. However, a fundamental paradox remains: when and how does this essential homeostatic system collapse to trigger a self- destructive viral mimicry response?