Department of Neurology
Biochemical Phenomena, Metabolism, and Nutrition | Genetic Phenomena | Nervous System Diseases | Neuroscience and Neurobiology
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 alpha subunit of eukaryotic initiation factor-2 (eIF2alpha), the core event of an integrated stress response (ISR). Compounds inhibiting phospho-eIF2alpha-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.
Neurodegenerative diseases, Translation
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DOI of Published Version
Nat Commun. 2018 Jan 4;9(1):51. doi: 10.1038/s41467-017-02495-z. Link to article on publisher's site
Cheng, Weiwei; Wang, Shaopeng; Mestre, Alexander A.; Fu, Chenglai; Makarem, Andres; Xian, Fengfan; Hayes, Lindsey R.; Lopez-Gonzalez, Rodrigo; Drenner, Kevin; Jiang, Jie; Cleveland, Don W.; and Sun, Shuying, "C9ORF72 GGGGCC repeat-associated non-AUG translation is upregulated by stress through eIF2alpha phosphorylation" (2018). Open Access Articles. 3375.
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This work is licensed under a Creative Commons Attribution 4.0 License.