eIF4B and eIF4H mediate GR production from expanded G4C2 in a Drosophila model for C9orf72-associated ALS

Lindsey D. Goodman, Mercedes Prudencio, Ananth R. Srinivasan, Olivia M. Rifai, Virginia M.Y. Lee, Leonard Petrucelli, Nancy M. Bonini

Research output: Contribution to journalArticle

Abstract

The discovery of an expanded (GGGGCC)n repeat (termed G4C2) within the first intron of C9orf72 in familial ALS/FTD has led to a number of studies showing that the aberrant expression of G4C2 RNA can produce toxic dipeptides through repeat-associated non-AUG (RAN-) translation. To reveal canonical translation factors that impact this process, an unbiased loss-of-function screen was performed in a G4C2 fly model that maintained the upstream intronic sequence of the human gene and contained a GFP tag in the GR reading frame. 11 of 48 translation factors were identified that impact production of the GR-GFP protein. Further investigations into two of these, eIF4B and eIF4H, revealed that downregulation of these factors reduced toxicity caused by the expression of expanded G4C2 and reduced production of toxic GR dipeptides from G4C2 transcripts. In patient-derived cells and in post-mortem tissue from ALS/FTD patients, eIF4H was found to be downregulated in cases harboring the G4C2 mutation compared to patients lacking the mutation and healthy individuals. Overall, these data define eIF4B and eIF4H as disease modifiers whose activity is important for RAN-translation of the GR peptide from G4C2-transcripts.

Original languageEnglish (US)
Number of pages1
JournalActa Neuropathologica Communications
Volume7
Issue number1
DOIs
StatePublished - Apr 25 2019

Fingerprint

Drosophila
Dipeptides
Poisons
Down-Regulation
Reading Frames
Mutation
Diptera
Introns
RNA
Peptides
Genes
eIF-4B
Proteins

Keywords

  • Amyotrophic lateral sclerosis (ALS) (Lou Gehrig disease)
  • C9orf72
  • Drosophila
  • eIF4B
  • eIF4H
  • Neurodegeneration
  • RAN-translation

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

Cite this

eIF4B and eIF4H mediate GR production from expanded G4C2 in a Drosophila model for C9orf72-associated ALS. / Goodman, Lindsey D.; Prudencio, Mercedes; Srinivasan, Ananth R.; Rifai, Olivia M.; Lee, Virginia M.Y.; Petrucelli, Leonard; Bonini, Nancy M.

In: Acta Neuropathologica Communications, Vol. 7, No. 1, 25.04.2019.

Research output: Contribution to journalArticle

Goodman, Lindsey D. ; Prudencio, Mercedes ; Srinivasan, Ananth R. ; Rifai, Olivia M. ; Lee, Virginia M.Y. ; Petrucelli, Leonard ; Bonini, Nancy M. / eIF4B and eIF4H mediate GR production from expanded G4C2 in a Drosophila model for C9orf72-associated ALS. In: Acta Neuropathologica Communications. 2019 ; Vol. 7, No. 1.
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