Investigating the role of transposable elements in physiological and pathological genetic and molecular mechanisms involved in the development of the nervous system in animal models. Searching for pathways and future therapies for neurological diseases.

Transposable elements (TEs) are major components of eukaryotic genomes. However, the extent of their impact on genome evolution, function, and disease remains not totally ascertained. A deregulation of TEs has been related to neurodevelopmental diseases in human brains and in mouse models. A role for transposon deregulation has also been suggested for neurodegenerative diseases including the amyotrophic lateral sclerosis (ALS) caused by functional alterations of the RNA/DNA binding protein TDP-43. The correct regulation of transposable elements occurs by the piRNA pathway with an established role in the germline tissues even though a role of the so called piRNA in somatic and nervous tissues is still under investigation. A rare neurological disease, in which transposon dis-regulation, piRNA pathway and neurological defects are put together, is Fragile X Syndrome (FXS). Drosophila and mouse are validated animal models for studies on neurological diseases. In this project we propose do deepen and clarify the relationship between the regulation of transposable elements and the development of the nervous system in normal condition as well as in mutants of the gene responsible for the syndrome (FraX) in Drosophila melanogaster and in the mouse (Fmr1).  The starting points of the proposed project is the activation of transposable elements in nervous tissues of Drosophila melanogaster wild type at a precise point during development demonstrating a physiological role of TEs in a time window during development of the nervous system; intriguingly, this peak is altered in dFmr1 mutants, as shown in Figure 1. In addition to these preliminary but reproducible results we base this proposal also on: i) the demonstration of the role of the dFmr1 gene in the piRNA pathway occurring in Drosophila gonads and regulating the transposable elements; ii) the biochemical and genetic interaction of dFmr1 protein with some Argonaute proteins in the gonads and also at the neuromuscular junctions; iii) the deregulation of transposons in mutants of a gene regulating the circadian rhythms, our hypothesis. The study of Fragile X syndrome is the point of contact between our group and prof. Ciranna’s group whose studies on the Fmr1-KO mouse model have demonstrated that activation of  5-HT₇ receptors for Serotonin (5-hydroxytryptamine, 5-HT), corrects abnormal synaptic plasticity in a mouse model of FXS, opening new perspectives for therapy. In the proposed project we will definitely analyse the physiological role of TEs during the development of wild type Drosophila and mouse as well as in mutants that are models for neurological diseases. We also will analyse Drosophila and mice grown on Cadmium, producing neurological phenotypes. With different approaches we will identify specific pathways involved in the physiological and “pathological” activation of TEs during development of the nervous system in Drosophila and in mouse. We also will test mice treated with molecules compared with wild type for the deregulation of TEs expression as well as for timing of the peak appearance. Furthermore, we will test the possibility to rescue synaptic plasticity, learning and behaviour in Fmr1 KO mice using molecules that increase intracellular cyclic AMP levels, a pathway which is downregulated in FXS models as well as in FXS patients. The results of this projects will add specific and useful knowledge on the molecular and physiological mechanisms of at least some neurological diseases with a devastating impact on families and society.

• Drosophila Melanogaster
• Transposons
• Fragile X Syndrome
• piRNA pathway
• 5-HT
• PACAP