Fig. 5.

PKR activation model of RAN translation. Schematic diagram depicting chronic activation of PKR by repeat expansion RNAs increases RAN translation. Blocking the PKR pathway with PKR-K296R, metformin, or TRBP reduces RAN protein levels to a greater extent than blocking p-eIF2α with ISRIB. These results suggest PKR regulates RAN protein levels through both p-eIF2α–dependent and p-eIF2α–independent pathways. The accumulation of misfolded or aggregated RAN proteins may, in turn, activate the PERK pathway and exacerbate disease by leading to further eIF2α phosphorylation and a cycle of increased RAN protein production.