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Rodriguez S, Sahin A, Schrank BR, Al-Lawati H, Costantino I, Benz E, Fard D, Albers AD, Cao L, Gomez AC, Evans K, Ratti E, Cudkowicz M, Frosch MP, Talkowski M, Sorger PK, Hyman BT, Albers MW. Genome-encoded cytoplasmic double-stranded RNAs, found in C9ORF72 ALS-FTD brain, propagate neuronal loss. Sci Transl Med. 2021 Jul 7;13(601) PubMed.
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Boston University School of Medicine
The work from the Albers group presents an additional mechanism through which the hexanucleotide expansions of C9ORF72 can mediate cell death. The group began by studying motor cortices (and frontal cortices) from ALS/FTD C9ORF72 patients and observed the presence of cytoplasmic double-stranded RNA (cdsRNA) that co-localized with TDP-43 pathology. This data suggests that TDP-43 pathology correlates with cdsRNA, but does not show the converse because it is unclear what fraction of cells had cdsRNA pathology but no TDP-43 pathology.
Immunoblotting and transcriptome analysis suggested that the cdsRNA induced an IFN-I response, which is consistent with known responses to cdsRNA. The group went on to show that expression of 66mer G4C2 repeat sequences induces a similar IFN response and some cell death; the response depended on the presence of cdsRNA but could be elicited with cdsRNA from transcripts unrelated to G4C2, such as GFP cdsRNA.
The lack of specificity for G4C2 is an important caveat, because mitochondrial damage is known to release dsRNA into the cytoplasm, creating cdsRNA. Because of this, it is not uncommon to observe an IFN response in the face of cell toxicity.
Regardless of the source of the cdsRNA, its presence can be problematic. The Albers group addressed this by inhibiting different kinases regulating the IFN pathway. They examined PKR inhibitors, but found those to be toxic. On the other hand, JAK inhibitors nicely rescued the toxicity. This raises the possibility that brain-penetrant JAK inhibitors might have some value in treating C9ORF72 ALS/FTD, which is a potentially important contribution.
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