| Autor: |
Steven Rodriguez, Al-Lawati H, Elena Ratti, Benjamin R. Schrank, Eric G. Benz, Alefiya Dhilla Albers, Michael E. Talkowski, Matthew P. Frosch, Asli Sahin, Alexis C. Gomez, Isabel Costantino, B. T. Hyman, Mark W. Albers, Peter K. Sorger, Luxiang Cao, Fard D, Merit Cudkowicz |
| Rok vydání: |
2018 |
| Předmět: |
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| Popis: |
SUMMARYInnate 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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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