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

journal_name

Nat Commun

journal_title

Nature communications

authors

Cheng W,Wang S,Mestre AA,Fu C,Makarem A,Xian F,Hayes LR,Lopez-Gonzalez R,Drenner K,Jiang J,Cleveland DW,Sun S

doi

10.1038/s41467-017-02495-z

subject

Has Abstract

pub_date

2018-01-04 00:00:00

pages

51

issue

1

issn

2041-1723

pii

10.1038/s41467-017-02495-z

journal_volume

9

pub_type

杂志文章

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