eIF4B and eIF4H mediate GR production from expanded G4C2 in a Drosophila model for C9orf72-associated ALS
| Autor: | Ananth R. Srinivasan, Mercedes Prudencio, Nancy M. Bonini, Leonard Petrucelli, Olivia M. Rifai, Lindsey D. Goodman, Virginia M.-Y. Lee |
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| Rok vydání: | 2019 |
| Předmět: |
Male
0301 basic medicine RAN-translation Biology medicine.disease_cause lcsh:RC346-429 Pathology and Forensic Medicine Animals Genetically Modified 03 medical and health sciences Cellular and Molecular Neuroscience 0302 clinical medicine Downregulation and upregulation C9orf72 medicine Animals Humans Amyotrophic lateral sclerosis (ALS) (Lou Gehrig disease) Eukaryotic Initiation Factors EIF4B Gene lcsh:Neurology. Diseases of the nervous system Genetics Mutation DNA Repeat Expansion C9orf72 Protein Amyotrophic Lateral Sclerosis Intron RNA Translation (biology) Dipeptides Disease Models Animal eIF4H 030104 developmental biology Gene Expression Regulation eIF4B Female Drosophila Neurology (clinical) 030217 neurology & neurosurgery |
| Zdroj: | Acta Neuropathologica Communications, Vol 7, Iss 1, Pp 1-16 (2019) |
| ISSN: | 2051-5960 |
| DOI: | 10.1186/s40478-019-0711-9 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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