4.4 Article

Ribosome profiling reveals novel regulation of C9ORF72 GGGGCC repeat-containing RNA translation

Journal

RNA
Volume 28, Issue 2, Pages 123-138

Publisher

COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1261/rna.078963.121

Keywords

ALS; C9ORF72; DAP5; frontotemporal dementia; ribosome profiling; ribosome stalling; uORF translation

Funding

  1. TARGET ALS
  2. Muscular Dystrophy Association
  3. National Institutes of Health (NIH) [R21NS109847]
  4. NIH [R21NS109847, R01GM46779, R01GM135087, R01CA207893, R01CA248397, R37NS057553, R01NS101986, R21NS112766, R21NS119952]

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GGGGCC (G(4)C(2)) repeat expansion in the first intron of C9ORF72 leads to amyotrophic lateral sclerosis and frontotemporal dementia. The repeated RNA is translated into neurotoxic DPR proteins. It was found that there are three translation initiation sites in the intron upstream of the (G(4)C(2)) repeats, and ribosomes are stalled on the repeats during translocation. Additionally, the translation process is inhibited by a uORF in the preceding exon.
GGGGCC (G(4)C(2)) repeat expansion in the first intron of C9ORF72 causes amyotrophic lateral sclerosis and frontotemporal dementia. Repeat-containing RNA is translated into dipeptide repeat (DPR) proteins, some of which are neurotoxic. Using dynamic ribosome profiling, we identified three translation initiation sites in the intron upstream of (G(4)C(2)) repeats; these sites are detected irrespective of the presence or absence of the repeats. During translocation, ribosomes appear to be stalled on the repeats. An AUG in the preceding C9ORF72 exon initiates a uORF that inhibits downstream translation. Polysome isolation indicates that unspliced (G(4)C(2)) repeat-containing RNA is a substrate for DPR protein synthesis. (G(4)C(2)) repeat-containing RNA translation is 5 ' cap-independent but inhibited by the initiation factor DAP5, suggesting an interplay with uORF function. These results define novel translational mechanisms of expanded (G(4)C(2)) repeat-containing RNA in disease.

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