A supplement for myotonic dystrophy

An international team of researchers coordinated by Sapienza University of Rome, in collaboration with the Pasteur Institute Italy - Cenci Bolognetti Foundation and other foreign research centres, have published a study in eLife that contributes to the understanding of the mechanisms underlying myotonic dystrophy, opening up new possible therapeutic perspectives

A group of international researchers, led by the Departments of Molecular Medicine and Biology and Biotechnology "Charles Darwin" of Sapienza University of Rome, together with the Pasteur Institute Italy - Cenci Bolognetti Foundation and other international research centres, have published a paper in the journal e-Life that contributes to the understanding of the pathogenetic basis of myotonic dystrophy type 2 (DM2), also opening possible new diagnostic and therapeutic frontiers.

Myotonic dystrophy (MD) is an autosomal dominant genetic disorder characterised by muscle weakness, early cataracts, myotonia and multi-system involvement. There are two forms: myotonic dystrophy type 1 or DM1, due to a mutation in the DMPK gene, and DM2, in which the mutation is in the CNBP/ZNF9 gene. Although the genetic abnormalities responsible for this highly disabling disease are known, the mechanisms underlying its clinical manifestations are still unclear, and, unfortunately, there is still no effective therapy available to alleviate its symptoms.

In this research, funded by the AFM-Telethon Foundation and the Istituto Pasteur Italia-Fondazione Cenci Bolognetti, the specific role of the CNBP (Nucleic Acid-Binding Protein) protein in muscle was addressed for the first time: By carrying out gene inactivation and reactivation studies in the common fruit fly (Drosophila melanogaster), the researchers realised that it is the lack of this protein, produced from the CNBP gene in muscles, that causes locomotor deficits similar to those observed in human pathology, as well as a reduced ability to fly in the insect.

The work showed that this deficit causes a reduction in an enzyme, ornithine decarboxylase (ODC), which regulates the production of polyamines (putrescine, spermidine, spermine), small positively charged molecules that are essential for many vital functions in the cell. Polyamine spermidine, in particular, is a food supplement that has recently become the subject of numerous studies for its alleged ability to prevent ageing and certain degenerative diseases, both cardiac and neurological.

"In our work," says Laura Ciapponi of the Sapienza Department of Biology and Biotechnology "Charles Darwin", one of the study coordinators, "we have shown that CNBP depletion in Drosophila muscles causes age-dependent locomotor defects, which are related to altered polyamine metabolism."

Indeed, the research team observed a significant reduction in CNBP, ODC and polyamines both in fruit flies lacking the CNBP gene and in the muscles of DM2 patients. "Surprisingly," concludes Gianluca Canettieri of the Department of Molecular Medicine, "when we administered polyamines, including the supplement spermidine, to our study models, we observed a significant improvement in locomotor deficits."

According to the authors, since the reduction of polyamines is also present in the muscles of DM2 patients, these observations open up new diagnostic and therapeutic perspectives for patients suffering from this disabling disease.

References:

Translational control of polyamine metabolism by CNBP is required for Drosophila locomotor function - Sonia Coni, Federica A Falconio, Marta Marzullo, Marzia Munafò, Benedetta Zuliani, Federica Mosti, Alessandro Fatica, Zaira Ianniello, Rosa Bordone, Alberto Macone, Enzo Agostinelli, Alessia Perna, Tanja Matkovic, Stephan Sigrist, Gabriella Silvestri, Gianluca Canettieri, Laura Ciapponi - eLife, 2021. DOI: https://doi.org/10.7554/eLife.69269