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

Steven Rodriguez, Benjamin R. Schrank, Asli Sahin, Hawra Al-Lawati, Isabel Costantino, Eric Benz, Darian Fard, View ORCID ProfileAlefiya D. Albers, Luxiang Cao, Alexis C. Gomez, Elena Ratti, Merit Cudkowicz, Matthew P. Frosch, Michael Talkowski, Peter K. Sorger, Bradley T. Hyman, Mark W. Albers
doi: https://doi.org/10.1101/248328
Steven Rodriguez
1Department of Neurology, Massachusetts General Hospital, Boston, MA
55Harvard Program in Therapeutic Science, Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA 02115
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Benjamin R. Schrank
1Department of Neurology, Massachusetts General Hospital, Boston, MA
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Asli Sahin
1Department of Neurology, Massachusetts General Hospital, Boston, MA
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Hawra Al-Lawati
1Department of Neurology, Massachusetts General Hospital, Boston, MA
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Isabel Costantino
1Department of Neurology, Massachusetts General Hospital, Boston, MA
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Eric Benz
1Department of Neurology, Massachusetts General Hospital, Boston, MA
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Darian Fard
1Department of Neurology, Massachusetts General Hospital, Boston, MA
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Alefiya D. Albers
1Department of Neurology, Massachusetts General Hospital, Boston, MA
2Department of Psychology, Endicott College, Beverly MA
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  • ORCID record for Alefiya D. Albers
Luxiang Cao
1Department of Neurology, Massachusetts General Hospital, Boston, MA
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Alexis C. Gomez
1Department of Neurology, Massachusetts General Hospital, Boston, MA
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Elena Ratti
1Department of Neurology, Massachusetts General Hospital, Boston, MA
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Merit Cudkowicz
1Department of Neurology, Massachusetts General Hospital, Boston, MA
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Matthew P. Frosch
3Department of Pathology, Massachusetts General Hospital, Boston, MA
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Michael Talkowski
4Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA
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Peter K. Sorger
55Harvard Program in Therapeutic Science, Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA 02115
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Bradley T. Hyman
55Harvard Program in Therapeutic Science, Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA 02115
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Mark W. Albers
1Department of Neurology, Massachusetts General Hospital, Boston, MA
55Harvard Program in Therapeutic Science, Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA 02115
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SUMMARY

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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Posted January 19, 2018.
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Genome-Encoded Cytoplasmic Double-Stranded RNAs, Found in C9ORF72 ALS-FTD Brain, Provoke Propagated Neuronal Death
Steven Rodriguez, Benjamin R. Schrank, Asli Sahin, Hawra Al-Lawati, Isabel Costantino, Eric Benz, Darian Fard, Alefiya D. Albers, Luxiang Cao, Alexis C. Gomez, Elena Ratti, Merit Cudkowicz, Matthew P. Frosch, Michael Talkowski, Peter K. Sorger, Bradley T. Hyman, Mark W. Albers
bioRxiv 248328; doi: https://doi.org/10.1101/248328
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Genome-Encoded Cytoplasmic Double-Stranded RNAs, Found in C9ORF72 ALS-FTD Brain, Provoke Propagated Neuronal Death
Steven Rodriguez, Benjamin R. Schrank, Asli Sahin, Hawra Al-Lawati, Isabel Costantino, Eric Benz, Darian Fard, Alefiya D. Albers, Luxiang Cao, Alexis C. Gomez, Elena Ratti, Merit Cudkowicz, Matthew P. Frosch, Michael Talkowski, Peter K. Sorger, Bradley T. Hyman, Mark W. Albers
bioRxiv 248328; doi: https://doi.org/10.1101/248328

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