Genome-encoded cytoplasmic double-stranded RNAs, found in C9ORF72 ALS-FTD brain, propagate neuronal loss
基因
遗传学
三核苷酸重复扩增
作者
Steven Rodriguez,Asli Sahin,Benjamin R. Schrank,Hawra Al-Lawati,Isabel Costantino,Eric B. Benz,Darian Fard,Alefiya Dhilla Albers,Luxiang Cao,Alexis C. Gomez,Kyle Evans,Elena Ratti,Merit Cudkowicz,Matthew P. Frosch,Michael E. Talkowski,Peter K. Sorger,Bradley T. Hyman,Mark W. Albers
出处
期刊:Science Translational Medicine [American Association for the Advancement of Science (AAAS)] 日期:2021-07-07卷期号:13 (601)被引量:2
标识
DOI:10.1126/scitranslmed.aaz4699
摘要
Triggers of innate immune signaling in the CNS of patients with amyotrophic lateral sclerosis and frontotemporal degeneration (ALS/FTD) remain elusive. We report the presence of cytoplasmic double-stranded RNA (cdsRNA), an established trigger of innate immunity, in ALS-FTD brains carrying C9ORF72 intronic hexanucleotide expansions that included genomically encoded expansions of the G4C2 repeat sequences. The presence of cdsRNA in human brains was coincident with cytoplasmic TAR DNA binding protein 43 (TDP-43) inclusions, a pathologic hallmark of ALS/FTD. Introducing cdsRNA into cultured human neural cells induced type I interferon (IFN-I) signaling and death that was rescued by FDA-approved JAK inhibitors. In mice, genomically encoded dsRNAs expressed exclusively in a neuronal class induced IFN-I and death in connected neurons non-cell-autonomously. Our findings establish that genomically encoded cdsRNAs trigger sterile, viral-mimetic IFN-I induction and propagated death within neural circuits and may drive neuroinflammation and neurodegeneration in patients with ALS/FTD.