Translational control of polyamine metabolism by cnbp is required for drosophila locomotor function

Gabriella Silvestri, Alessia Perna, Sonia Coni, Federica A. Falconio, Marta Marzullo, Marzia Munafò, Benedetta Zuliani, Federica Mosti, Alessandro Fatica, Zaira Ianniello, Rosa Bordone, Alberto Macone, Enzo Agostinelli, Tanja Matkovic, Stephan Sigrist, Gianluca Canettieri, Laura Ciapponi

Risultato della ricerca: Contributo in rivistaArticolo in rivista

Abstract

Microsatellite expansions of CCTG repeats in the cellular nucleic acid-binding protein (CNBP) gene leads to accumulation of toxic RNA and have been associated with myotonic dystrophy type 2 (DM2). However, it is still unclear whether the dystrophic phenotype is also linked to CNBP decrease, a conserved CCHC-type zinc finger RNA-binding protein that regulates translation and is required for mammalian development. Here, we show that depletion of Drosophila CNBP in muscles causes ageing-dependent locomotor defects that are correlated with impaired polyamine metabolism. We demonstrate that the levels of ornithine decarboxylase (ODC) and polyamines are significantly reduced upon dCNBP depletion. Of note, we show a reduction of the CNBP-polyamine axis in muscles from DM2 patients. Mechanistically, we provide evidence that dCNBP controls polyamine metabolism through binding dOdc mRNA and regulating its translation. Remarkably, the locomotor defect of dCNBP-deficient flies is rescued by either polyamine supplementation or dOdc1 overexpression. We suggest that this dCNBP function is evolutionarily conserved in vertebrates with relevant implications for CNBP-related pathophysiological conditions.
Lingua originaleEnglish
pagine (da-a)69269-N/A
RivistaeLife
Volume10
DOI
Stato di pubblicazionePubblicato - 2021

Keywords

  • Animals
  • Animals, Genetically Modified
  • CNBP
  • Cell Line
  • D. melanogaster
  • Down-Regulation
  • Drosophila Proteins
  • Drosophila melanogaster
  • Gene Expression Regulation
  • HEK293 Cells
  • Humans
  • Motor Activity
  • Muscle, Skeletal
  • Myotonic Dystrophy
  • ODC
  • Polyamines
  • Protein Biosynthesis
  • Putrescine
  • RNA Interference
  • RNA-Binding Proteins
  • Spermidine
  • genetics
  • genomics
  • human
  • myotonic dystrophy 2
  • neuroscience
  • polyamine
  • translation

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