Transcriptomic profiling of purified mature olfactory sensory neurons from transgenic mice expressing genomically encoded double-stranded RNA

Triggers 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 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. Overall design: mRNA profiling of mature olfactory sensory neurons from transgenic mouse lines with neurodegeneration purified by fluorescence-activated cell sorting