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.