The second half of Kevin’s postdoctoral work is now available on bioRxiv. In this work, we describe how neuronal aging leads to the accumulation of double-stranded RNA. This double-stranded RNA binds to the stress-responsive kinase PKR, which in turn triggers chronic stress in aged neurons. The source of endogenous double-stranded RNA is bidirectional transcription of the mitochondrial transcription, accounting for over 80% of dsRNA-seq reads in transdifferentiated neurons and a similarly high fraction in the aging human brain. We show that mitochondrial double-stranded RNA is able to leak from damaged mitochondria, and we were able to recreate this phenotype in young neurons by artificially damaging the mitochondria. Inhibiting the PKR-mediated stress response restores normal translation in aged neurons, offering a potential therapeutic angle for neuronal aging and neurodegenerative diseases. We are excited to follow up on this work in the lab!
Figure 6. Our results indicate that neuronal aging leads to (1) MT-dsRNA release, (2) PKR activation, and (3) stress granule assembly. The chronic stress response can be ablated in aged neurons with PKR inhibitor or induced in young neurons with Antimycin A.