C9ORF72 GGGGCC repeat-associated non-AUG translation is upregulated by stress through eIF2? phosphorylation.

ABSTRACT: Hexanucleotide repeat expansion in C9ORF72 is the most frequent cause of both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here we demonstrate that the repeat-associated non-AUG (RAN) translation of (GGGGCC) n -containing RNAs into poly-dipeptides can initiate in vivo without a 5'-cap. The primary RNA substrate for RAN translation of C9ORF72 sense repeats is shown to be the spliced first intron, following its excision from the initial pre-mRNA and transport to the cytoplasm. Cap-independent RAN translation is shown to be upregulated by various stress stimuli through phosphorylation of the ? subunit of eukaryotic initiation factor-2 (eIF2?), the core event of an integrated stress response (ISR). Compounds inhibiting phospho-eIF2?-signaling pathways are shown to suppress RAN translation. Since the poly-dipeptides can themselves induce stress, these findings support a feedforward loop with initial repeat-mediated toxicity enhancing RAN translation and subsequent production of additional poly-dipeptides through ISR, thereby promoting progressive disease.

SUBMITTER: Cheng W 

PROVIDER: S-EPMC5754368 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature