Rodriguez, SteveSahin, AsliSchrank, Benjamin R.Al Lawati, HawraCostantino, IsabelBenz, EricFard, DarianAlbers, AlefiyaCao, LuxiangGomez, AlexisEvans, KyleRatti, ElenaCudkowicz, MeritFrosch, MatthewTalkowski, MichaelSorger, PeterHyman, BradleyAlbers, Mark2022-08-312021-07-07Rodriguez, Steven, Asli Sahin, Benjamin R Schrank, Hawra Al-Lawati, Isabel Costantino, Eric Benz, Darian Fard, et al. 2021. “Genome-Encoded Cytoplasmic Double-Stranded RNAs, Found in C9ORF72 ALS-FTD Brain, Propagate Neuronal Loss.” Science Translational Medicine 13 (601): 1.https://nrs.harvard.edu/URN-3:HUL.INSTREPOS:37373107NATriggers of innate immune signaling in the CNS of amyotrophic lateral sclerosis and frontotemporal degeneration (ALS/FTD) patients remain elusive. We report the presence of cytoplasmic double-stranded RNA (cdsRNA), an established trigger of innate immunity, in ALS-FTD brains carrying C9ORF72 intronic hexanucleotide expansions that included genomically encoded expansions of the G4C2 repeat sequences. 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 ALS/FTD patients.en-USJournal Article2022-08-3110.1126/scitranslmed.aaz4699