Genome-encoded cytoplasmic double-stranded RNAs, found in C9ORF72 ALS-FTD brain, propagate neuronal loss

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Science Translational Medicine  07 Jul 2021:
Vol. 13, Issue 601, eaaz4699
DOI: 10.1126/scitranslmed.aaz4699

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Targeting interferon triggers in ALS/FTD

C9ORF72 repeat expansions are among the most important genetic cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Increased activation of the type 1 interferon (IFN1) signaling in ALS/FTD brain contributes to disease pathophysiology. However, the mechanisms mediating IFN1 activation are unclear. Here, Rodriguez et al. showed that cytoplasmatic double-stranded RNA (cdsRNA) derived from G4C2 expansions was elevated in brains of patients with C9ORF72-associated ALS/FTD. In preclinical in vitro and in vivo models, cdsRNA induced IFN1 signaling and cell death that was reduced by treatment with JAK inhibitors. The results suggest that targeting JAK might be beneficial in C9ORF72-associated ALS/FTD.


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.

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