Format

Send to

Choose Destination
Nat Commun. 2018 Jan 4;9(1):51. doi: 10.1038/s41467-017-02495-z.

C9ORF72 GGGGCC repeat-associated non-AUG translation is upregulated by stress through eIF2α phosphorylation.

Author information

1
Department of Pathology and Brain Science Institute, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
2
The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
3
Brain Science Institute and Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
4
Department of Neurology, University of Massachusetts Medical School, Worcester, MA, 01605, USA.
5
Ludwig Institute for Cancer Research and Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA, 92093, USA.
6
Department of Pathology and Brain Science Institute, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. shuying.sun@jhmi.edu.

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 α subunit of eukaryotic initiation factor-2 (eIF2α), the core event of an integrated stress response (ISR). Compounds inhibiting phospho-eIF2α-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.

PMID:
29302060
PMCID:
PMC5754368
DOI:
10.1038/s41467-017-02495-z
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center