A C. elegans model of C9orf72-associated ALS/FTD uncovers a conserved role for eIF2D in RAN translation.

Autor: Sonobe Y; University of Chicago Medical Center, 5841S. Maryland Avenue, Chicago, IL, 60637, USA.; Department of Neurology, University of Chicago Medical Center, 5841S. Maryland Avenue, Chicago, IL, 60637, USA.; The Grossman Institute for Neuroscience, Quantitative Biology, and Human Behavior, University of Chicago, Chicago, IL, USA., Aburas J; University of Chicago Medical Center, 5841S. Maryland Avenue, Chicago, IL, 60637, USA.; The Grossman Institute for Neuroscience, Quantitative Biology, and Human Behavior, University of Chicago, Chicago, IL, USA.; Department of Neurobiology, University of Chicago, Chicago, IL, USA., Krishnan G; Department of Neurology, University of Massachusetts Medical School, Worcester, MA, 01605, USA., Fleming AC; The Ken & Ruth Davee Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, USA., Ghadge G; University of Chicago Medical Center, 5841S. Maryland Avenue, Chicago, IL, 60637, USA.; Department of Neurology, University of Chicago Medical Center, 5841S. Maryland Avenue, Chicago, IL, 60637, USA.; The Grossman Institute for Neuroscience, Quantitative Biology, and Human Behavior, University of Chicago, Chicago, IL, USA., Islam P; MRC London Institute of Medical Sciences, London, UK.; Institute of Clinical Sciences, Imperial College London, London, UK., Warren EC; MRC London Institute of Medical Sciences, London, UK.; Institute of Clinical Sciences, Imperial College London, London, UK., Gu Y; Neuromuscular & Movement Disorders, Biogen, Cambridge, MA, 02142, USA., Kankel MW; Neuromuscular & Movement Disorders, Biogen, Cambridge, MA, 02142, USA., Brown AEX; MRC London Institute of Medical Sciences, London, UK.; Institute of Clinical Sciences, Imperial College London, London, UK., Kiskinis E; The Ken & Ruth Davee Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, USA., Gendron TF; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA., Gao FB; Department of Neurology, University of Massachusetts Medical School, Worcester, MA, 01605, USA., Roos RP; University of Chicago Medical Center, 5841S. Maryland Avenue, Chicago, IL, 60637, USA. rroos@neurology.bsd.uchicago.edu.; Department of Neurology, University of Chicago Medical Center, 5841S. Maryland Avenue, Chicago, IL, 60637, USA. rroos@neurology.bsd.uchicago.edu.; The Grossman Institute for Neuroscience, Quantitative Biology, and Human Behavior, University of Chicago, Chicago, IL, USA. rroos@neurology.bsd.uchicago.edu., Kratsios P; University of Chicago Medical Center, 5841S. Maryland Avenue, Chicago, IL, 60637, USA. pkratsios@uchicago.edu.; The Grossman Institute for Neuroscience, Quantitative Biology, and Human Behavior, University of Chicago, Chicago, IL, USA. pkratsios@uchicago.edu.; Department of Neurobiology, University of Chicago, Chicago, IL, USA. pkratsios@uchicago.edu.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2021 Oct 15; Vol. 12 (1), pp. 6025. Date of Electronic Publication: 2021 Oct 15.
DOI: 10.1038/s41467-021-26303-x
Abstrakt: A hexanucleotide repeat expansion GGGGCC in the non-coding region of C9orf72 is the most common cause of inherited amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Toxic dipeptide repeats (DPRs) are synthesized from GGGGCC via repeat-associated non-AUG (RAN) translation. Here, we develop C. elegans models that express, either ubiquitously or exclusively in neurons, 75 GGGGCC repeats flanked by intronic C9orf72 sequence. The worms generate DPRs (poly-glycine-alanine [poly-GA], poly-glycine-proline [poly-GP]) and poly-glycine-arginine [poly-GR]), display neurodegeneration, and exhibit locomotor and lifespan defects. Mutation of a non-canonical translation-initiating codon (CUG) upstream of the repeats selectively reduces poly-GA steady-state levels and ameliorates disease, suggesting poly-GA is pathogenic. Importantly, loss-of-function mutations in the eukaryotic translation initiation factor 2D (eif-2D/eIF2D) reduce poly-GA and poly-GP levels, and increase lifespan in both C. elegans models. Our in vitro studies in mammalian cells yield similar results. Here, we show a conserved role for eif-2D/eIF2D in DPR expression.
(© 2021. The Author(s).)
Databáze: MEDLINE
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