Blocking RAN translation without altering repeat RNAs rescues C9ORF72 -related ALS and FTD phenotypes
Broad Institute · Harvard University · +11 more institutions
Abstract
GGGGCC (G 4 C 2 ) repeat expansion in C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Toxicity is thought to result from the accumulation of either repeat RNAs and/or dipeptide repeat proteins (DPRs) translated from repeat-containing transcripts through repeat-associated non-AUG (RAN) translation. To disentangle RNA from DPR toxicity, we mutated a CUG codon predominantly used to initiate DPR translation from all three reading frames. This mutation disrupted DPR synthesis while preserving the expression of repeat-containing RNAs. Despite the accumulation of RNA foci, behavioral deficits and pathological abnormalities, including p-TDP-43…
Citation impact
- FWCI
- 67.86
- Percentile
- 99%
- References
- 110
Authors
46- XJXin JiangCorresponding
Broad Institute, Harvard University, Massachusetts General Hospital
- LSLaure Schaeffer
Centre National de la Recherche Scientifique, Architecture et Réactivité de l'arN
- DPDivya Patni
Harvard University, Massachusetts General Hospital
- TRTommaso Russo
Harvard University, Vita-Salute San Raffaele University, Massachusetts General Hospital, IRCCS Ospedale San Raffaele
- CLChao-Zong Lee
Broad Institute, Harvard University, Massachusetts General Hospital
Topics & keywords
- Frontotemporal dementia
- C9orf72
- Translation (biology)
- Amyotrophic lateral sclerosis
- Trinucleotide repeat expansion
- Ran
- Phenotype
- RNA
- Quality Education