Pre-clinical identification of drugs targeting POLG disorders by using a Zebrafish/Yeast trans-species approach (ZIPPY)

Inside human cells there are organelles, called mitochondria, which perform the task of small energy plants. These organelles have their own genetic heritage, called mitochondrial DNA, whose quantity and integrity is maintained by the work of two proteins, POLG and POLG2. If, due to mutations, these two proteins do not work, a series of diseases is generated, collectively named POLG pathologies. These disorders can occur, depending on the case, with infantile epilepsies, liver failure, neuropathy, cardiomyopathy, dysfunction of ocular mobility, loss of coordination and muscle weakness. At present, there are no drugs to combat POLG pathologies, and their treatment is limited to symptom management. Our project intends to analyze a range of drugs that have already had positive effect on two very simple organisms, the yeast S. cerevisiae and the worm C. elegans. During our project, these drugs will be tested on new models for these diseases, which are equally miniaturized but much more complex, represented by zebrafish embryos, mutated in the corresponding POLG and POLG2 genes. Since our group has recently identified a drug with similar curative effects in yeast, worm and fish, this encourages us to attempt the enterprise by carrying out a large-scale test, looking for a greater number of molecules with therapeutic efficacy for POLG diseases.