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.
Highlights
Myotonic dystrophy (DM) is the most common inherited muscle dystrophy in adults and comprises two genetically distinct forms: DM type 1 (DM1, Steinert' disease, OMIM 160900), caused by an expansion of CTG repeats in the 3′ untranslated region of the DM protein kinase (DMPK) gene (Brook et al, 1992) and DM type 2 (DM2, OMIM 602668), due to the expansion of CCTG repeats in the first intron of the cellular nucleic acid-binding protein (CNBP) gene, named zinc finger protein 9 gene (ZNF9) (Liquori et al, 2001)
We demonstrate that the levels of ornithine decarboxylase (ODC) and polyamines are significantly reduced upon dCNBP depletion
We found that CNBP promotes IRES-mediated translation of ODC and polyamine metabolism in neurons and that this mechanism is aberrantly activated in the medulloblastoma (D’Amico et al, 2015)
Summary
Myotonic dystrophy (DM) is the most common inherited muscle dystrophy in adults and comprises two genetically distinct forms: DM type 1 (DM1, Steinert' disease, OMIM 160900), caused by an expansion of CTG repeats in the 3′ untranslated region of the DM protein kinase (DMPK) gene (Brook et al, 1992) and DM type 2 (DM2, OMIM 602668), due to the expansion of CCTG repeats in the first intron of the cellular nucleic acid-binding protein (CNBP) gene, named ZNF9 (Liquori et al, 2001) Both DM1 and DM2 display a multisystemic involvement of the skeletal muscle, heart, eye, brain, endocrine system and smooth muscle. The hypothesis that CNBP protein deficiency plays a key role in DM2 pathogenesis implies that perturbation of CNBP function contributes to this disease
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