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

Weiwei Cheng, Shaopeng Wang, Alexander A. Mestre, Chenglai Fu, Andres Makarem, Fengfan Xian, Lindsey R. Hayes, Rodrigo Lopez-Gonzalez, Kevin Drenner, Jie Jiang, Don W. Cleveland and Shuying Sun ()
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Weiwei Cheng: Johns Hopkins University School of Medicine
Shaopeng Wang: Johns Hopkins University School of Medicine
Alexander A. Mestre: Johns Hopkins University School of Medicine
Chenglai Fu: Johns Hopkins University School of Medicine
Andres Makarem: Johns Hopkins University School of Medicine
Fengfan Xian: Johns Hopkins University School of Medicine
Lindsey R. Hayes: Johns Hopkins University School of Medicine
Rodrigo Lopez-Gonzalez: University of Massachusetts Medical School
Kevin Drenner: University of California at San Diego
Jie Jiang: University of California at San Diego
Don W. Cleveland: University of California at San Diego
Shuying Sun: Johns Hopkins University School of Medicine

Nature Communications, 2018, vol. 9, issue 1, 1-12

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-017-02495-z

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