Poly-GR repeats associated with ALS/FTD gene C9ORF72 impair translation elongation and induce a ribotoxic stress response in neurons.

Hexanucleotide repeat expansion in the C9ORF72 gene is the most frequent inherited cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The expansion results in multiple dipeptide repeat proteins, among which arginine-rich poly-GR proteins are highly toxic to neurons and decrease the rate of protein synthesis. We investigated whether the effect on protein synthesis contributes to neuronal dysfunction and degeneration. We found that the expression of poly-GR proteins inhibited global translation by perturbing translation elongation. In iPSC-differentiated neurons, the translation of transcripts with relatively slow elongation rates was further slowed, and stalled, by poly-GR. Elongation stalling increased ribosome collisions and induced a ribotoxic stress response (RSR) mediated by ZAKα that increased the phosphorylation of the kinase p38 and promoted cell death. Knockdown of ZAKα or pharmacological inhibition of p38 ameliorated poly-GR–induced toxicity and improved the survival of iPSC–derived neurons from patients with C9ORF72-ALS/FTD. Our findings suggest that targeting the RSR may be neuroprotective in patients with ALS/FTD caused by repeat expansion in C9ORF72. Editor's summary: Repeat expansions in the gene C9ORF72 frequently cause the neurodegenerative diseases ALS and frontotemporal dementia. Using neurons derived from patients, Dong et al. found that repeats of glycine-arginine (poly-GR) encoded by mutant C9ORF72 RNA stalled the translational machinery, which caused ribosomes to collide. The resulting ribotoxic stress response induced neuronal death. Blocking this response by inhibiting the kinases ZAKα or p38 MAPK increased the survival of patient-derived neurons in culture. The approach might have therapeutic potential to preserve neurons in patients. —Leslie K. Ferrarelli [ABSTRACT FROM AUTHOR]