Translational control of polyamine metabolism by CNBP is required for Drosophila locomotor function

Abstract

Microsatellite expansions of CCTG repeats in the CNBP gene leads to accumulation of toxic RNA and have been associated to 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 age-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 muscle 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. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=195 SRC="FIGDIR/small/441910v2_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@a8c31corg.highwire.dtl.DTLVardef@1a18260org.highwire.dtl.DTLVardef@76a3d4org.highwire.dtl.DTLVardef@fdd041_HPS_FORMAT_FIGEXP M_FIG C_FIG CNBP controls muscle function by regulating the polyamine metabolism O_LILack of dCNBP impairs locomotor function through ODC-polyamine downregulation C_LIO_LIdCNBP binds dOdc mRNA and regulates its translation C_LIO_LIPolyamine supplementation or dOdc1 reconstitution rescues locomotor defects C_LIO_LICNBP-ODC-polyamine levels are reduced in muscle of DM2 patients C_LI