RT Journal Article
SR Electronic
T1 Genome-Encoded Cytoplasmic Double-Stranded RNAs, Found in C9ORF72 ALS-FTD Brain, Provoke Propagated Neuronal Death
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 248328
DO 10.1101/248328
A1 Rodriguez, Steven
A1 Schrank, Benjamin R.
A1 Sahin, Asli
A1 Al-Lawati, Hawra
A1 Costantino, Isabel
A1 Benz, Eric
A1 Fard, Darian
A1 Albers, Alefiya D.
A1 Cao, Luxiang
A1 Gomez, Alexis C.
A1 Ratti, Elena
A1 Cudkowicz, Merit
A1 Frosch, Matthew P.
A1 Talkowski, Michael
A1 Sorger, Peter K.
A1 Hyman, Bradley T.
A1 Albers, Mark W.
YR 2018
UL http://biorxiv.org/content/early/2018/01/19/248328.abstract
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.