Genome-encoded cytoplasmic double-stranded RNAs, found in <i>C9ORF72</i> ALS-FTD brain, propagate neuronal loss
Steven Rodriguez, Aslı Şahin, Benjamin R. Schrank, Hawra Al Lawati, Isabel Costantino, Eric Benz, Darian Fard, Alefiya Dhilla Albers, Luxiang Cao, Alexis C. Gomez, Kyle E. Evans, Elena Ratti, Merit Cudkowicz, Matthew P. Frosch, Michael E. Talkowski, Peter K. Sorger, Bradley T. Hyman, Mark W. Albers
Abstract
repeat sequences. The presence of cdsRNA in human brains was coincident with cytoplasmic TAR DNA binding protein 43 (TDP-43) inclusions, a pathologic hallmark of ALS/FTD. Introducing cdsRNA into cultured human neural cells induced type I interferon (IFN-I) signaling and death that was rescued by FDA-approved JAK inhibitors. In mice, genomically encoded dsRNAs expressed exclusively in a neuronal class induced IFN-I and death in connected neurons non-cell-autonomously. Our findings establish that genomically encoded cdsRNAs trigger sterile, viral-mimetic IFN-I induction and propagated death within neural circuits and may drive neuroinflammation and neurodegeneration in patients with ALS/FTD.