Genome-encoded Cytoplasmic Double-Stranded RNAs, Found in C9ORF72 ALS-FTD Brain, Provoke Propagated Neuronal Death

Rodriguez, S.; Schrank, B. R.; Sahin, A.; Al-Lawati, H.; Constantino, I.; Benz, E.; Fard, D.; Albers, A. D.; Cao, L.; Gomez, A. C.; Ratti, E.; Cudkowicz, M.; Frosch, M. P.; Talkowski, M.; Sorger, P. K.; Hyman, B. T.; Albers, M. W.

doi:10.1101/248328

bioRxiv · 10.1101/248328

Genome-encoded Cytoplasmic Double-Stranded RNAs, Found in C9ORF72 ALS-FTD Brain, Provoke Propagated Neuronal Death

Rodriguez, S.·Schrank, B. R.·Sahin, A.·Al-Lawati, H.·Constantino, I.·Benz, E.·Fard, D.·Albers, A. D.·Cao, L.·Gomez, A. C.·Ratti, E.·Cudkowicz, M.·Frosch, M. P.·Talkowski, M.·Sorger, P. K.·Hyman, B. T.·Albers, M. W.

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Abstract

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.

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Rodriguez, S., Schrank, B. R., Sahin, A., Al-Lawati, H., Constantino, I., Benz, E., Fard, D., Albers, A. D., Cao, L., Gomez, A. C., Ratti, E., Cudkowicz, M., Frosch, M. P., Talkowski, M., Sorger, P. K., Hyman, B. T., Albers, M. W.. 2018-01-19. Genome-encoded Cytoplasmic Double-Stranded RNAs, Found in C9ORF72 ALS-FTD Brain, Provoke Propagated Neuronal Death. https://doi.org/10.1101/248328

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