Translational control of polyamine metabolism by CNBP is required for Drosophila locomotor function
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Curated by eLife
Evaluation Summary:
This paper is of interest and relevance to clinicians and researchers in the field of muscular dystrophy, a condition that causes loss of muscle function and mobility primarily in older patients. The presented experiments suggest that at least part of the pathology of DM2, a certain form of muscular dystrophy, is caused by defects in a gene that is required for the production of small molecules, called polyamines which are known to support muscle health and function. Interestingly, in a Drosophila model of DM2, feeding with polyamines can restore muscle function. The paper gains broad interest by the demonstration that consistent with the findings in Drosophila, muscle biopsies from human DM2 patients show decreased ODC and polyamine levels, raising the possibility of using polyamines for therapy or prevention.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)
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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.
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Evaluation Summary:
This paper is of interest and relevance to clinicians and researchers in the field of muscular dystrophy, a condition that causes loss of muscle function and mobility primarily in older patients. The presented experiments suggest that at least part of the pathology of DM2, a certain form of muscular dystrophy, is caused by defects in a gene that is required for the production of small molecules, called polyamines which are known to support muscle health and function. Interestingly, in a Drosophila model of DM2, feeding with polyamines can restore muscle function. The paper gains broad interest by the demonstration that consistent with the findings in Drosophila, muscle biopsies from human DM2 patients show decreased ODC and polyamine levels, raising the possibility of using polyamines for therapy or prevention.
(This …
Evaluation Summary:
This paper is of interest and relevance to clinicians and researchers in the field of muscular dystrophy, a condition that causes loss of muscle function and mobility primarily in older patients. The presented experiments suggest that at least part of the pathology of DM2, a certain form of muscular dystrophy, is caused by defects in a gene that is required for the production of small molecules, called polyamines which are known to support muscle health and function. Interestingly, in a Drosophila model of DM2, feeding with polyamines can restore muscle function. The paper gains broad interest by the demonstration that consistent with the findings in Drosophila, muscle biopsies from human DM2 patients show decreased ODC and polyamine levels, raising the possibility of using polyamines for therapy or prevention.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)
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Joint Public Review:
The similar degenerative conditions DM1 and DM2 are respectively caused by tetranucleotide expansions in DMPK and CNBP encoding genes. This paper provides strong evidence that the disease mechanism underlying DM2 muscular dystrophy is mediated not just by the well accepted mechanism of pathogenic RNA transcribed from simple repeat sequences. The paper presents a detailed characterisation of multiple CNBP fly knock-down strains, all displaying similar motor impairments. The authors link the dysfunction to reduce translation of ODC, a key enzyme in polyamine metabolism, and to a reduction in putrescine. They go on to show that feeding putrescine or upregulating ODC can rescue the CNBP mutant defect. This strongly suggests that the primary reasons for the motor defects in CNBP mutants is a polyamine metabolism defect. …
Joint Public Review:
The similar degenerative conditions DM1 and DM2 are respectively caused by tetranucleotide expansions in DMPK and CNBP encoding genes. This paper provides strong evidence that the disease mechanism underlying DM2 muscular dystrophy is mediated not just by the well accepted mechanism of pathogenic RNA transcribed from simple repeat sequences. The paper presents a detailed characterisation of multiple CNBP fly knock-down strains, all displaying similar motor impairments. The authors link the dysfunction to reduce translation of ODC, a key enzyme in polyamine metabolism, and to a reduction in putrescine. They go on to show that feeding putrescine or upregulating ODC can rescue the CNBP mutant defect. This strongly suggests that the primary reasons for the motor defects in CNBP mutants is a polyamine metabolism defect. This is significant because polyamines such as putrescine and spermidine are important for muscle function. The experiments are well done, the data robust and convincing. What remains to be proven how well the Drosophila model mimics human disease and how relevant the CNBP - ODC - polyamine axis will prove to be to the pathology, therapy or prevention of human DM2.
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