Neurology/Neuroscience Research Seminar - Presented by Dr. Becky Glineburg, Research Fellow in the Todd Lab (UM Department of Neurology) and T32 trainee - Friday, April 26th

Nucleotide repeat expansion disorders and the integrated stress response

Abstract

Repeat associated non-AUG (RAN) translation at a number of nucleotide repeat expansions, including CGG repeats in the 5’ UTR of FMR1, and G4C2 repeats within C9orf72, are implicated in the pathogenesis of neurodegenerative disorders. The mechanisms by which this unconventional translation initiation occurs, and how this process and the resultant homo- and di-polypeptide products contribute to disease are not fully known. Cells exposed to stressors such as viral infection or misfolded proteins activate the integrated stress response (ISR), which suppresses global protein synthesis through phosphorylation of the initiation factor eIF2α, precluding initiator methionine tRNA incorporation into the preinitiation ribosomal complex. We previously found that RAN translation at both CGG and G4C2 repeats increases in response to ISR activation in a phosphor-eIF2α dependent manner. Furthermore, CGG and G4C2 repeats themselves induce stress granule formation and global translation inhibition. My current work focuses on identifying which ISR kinases are required for this stress response. I have found that the ISR kinase, PKR, typically activated by dsRNA, is phosphorylated in response to CGG and G4C2 repeat reporters. However, while knocking out or inhibiting PKR results in a decrease in stress granule formation in cells expressing either CGG or G4C2 repeats, only CGG RAN is selectively decreased upon these manipulations. These data suggest alternative mechanisms of stress activation and requirements of PKR in these two different disease contexts.