PT - JOURNAL ARTICLE AU - Rodriguez, Steven AU - Schrank, Benjamin R. AU - Sahin, Asli AU - Al-Lawati, Hawra AU - Costantino, Isabel AU - Benz, Eric AU - Fard, Darian AU - Albers, Alefiya D. AU - Cao, Luxiang AU - Gomez, Alexis C. AU - Ratti, Elena AU - Cudkowicz, Merit AU - Frosch, Matthew P. AU - Talkowski, Michael AU - Sorger, Peter K. AU - Hyman, Bradley T. AU - Albers, Mark W. TI - Genome-Encoded Cytoplasmic Double-Stranded RNAs, Found in C9ORF72 ALS-FTD Brain, Provoke Propagated Neuronal Death AID - 10.1101/248328 DP - 2018 Jan 01 TA - bioRxiv PG - 248328 4099 - http://biorxiv.org/content/early/2018/01/19/248328.short 4100 - http://biorxiv.org/content/early/2018/01/19/248328.full AB - Innate immune signaling activation and DNA damage are pathological hallmarks of aging that may herald multiple adult-onset neurodegenerative diseases. Here, we report that both cell autonomous and non-autonomous neuronal death are triggered by the production of cytoplasmic double-stranded RNA (cdsRNA) from a regulated, disarticulated transgene in the setting of type I interferon (IFN-I) signaling. CdsRNA is a pathogen associated molecular pattern that induces IFN-I in many cell types. Transfection of a dsRNA mimetic into cultured human neurons also induces IFN-I signaling and cell death in a dose-dependent manner. Direct relevance to human disease is found in neurons of ALS-FTD patients carrying C9ORF72 intronic hexanucleotide expansions; cdsRNA isolated from these tissues is comprised of repeat sequences. Together, these findings implicate cdsRNA generated from genomic sequences in neurons as a trigger for sterile, viral-mimetic IFN-I induction and propagated neuronal death within in a neural circuit in the aging nervous system.