Novel therapeutic targets in Fragile X Syndrome – NotifX

FMRP binds to thousands of specific mRNAs and regulates multiple aspects of their metabolism, particularly translation—including at the synaptic level—as well as their dendritic and axonal transport, stability, and localization, through precise spatiotemporal regulation. Several studies identifying FMRP-associated mRNAs indicate that certain signaling pathways—such as cAMP, cGMP, Ca²⁺, WNT, and cytoskeletal pathways—are strongly modulated by FMRP activity and become dysregulated in its absence. For this reason, we concentrated on specific RNA targets and the signaling pathways associated with them and investigated them using complementary approaches, including genetics, molecular biology, cell biology, electrophysiology, and behavioral analysis, in both animal and cellular models. This integrated approach increases our ability to better understand the molecular and cellular alterations observed in FXS neurons and their impact on behavior. In addition, we will aim to identify new signaling pathways associated with FMRP target mRNAs whose localization becomes altered in the absence of this protein.

Our research investigates biological mechanisms involved in neurodevelopmental disorders, including Fragile X syndrome. Using animal models, we identified genes and signaling pathways that influence social and cognitive functions. We found that specific molecular alterations affect neuronal communication, synaptic plasticity, and brain development. Importantly, correcting some of these alterations can improve behavioral outcomes in experimental models. These findings provide new insights into the mechanisms underlying these disorders and highlight potential molecular targets that could guide the development of future therapeutic strategies.

Since the start of the project, we have produced major publications revealing new mechanisms of neuronal migration, synaptic plasticity, and FMRP/PDE2A signaling pathways. These findings — including those from manuscripts currently in preparation — identify novel therapeutic targets, enhance our understanding of neurodevelopmental disorders, and contribute to the dissemination of knowledge within the international scientific community. Of particular note is the establishment of an industrial collaboration.

Fragile X Syndrome (FXS) is a neurodevelopmental disorder caused by the functional absence of FMRP, a protein involved in translational regulation of a subset of synaptic proteins. Our NotifX project aims at exploring novel aspects of its pathophysiology by focusing on two prominent targets of FMRP, PDE2A and APC, that modulate two critical pathways for FXS: cAMP and WNT. We propose:
1. To better characterize the altered associative memory formation in the hippocampal CA3 and olfactory bulb (OB) of the FXS mouse model and its link with the elevated expression of PDE2A and APC;
2. To understand the role of PDE2A and APC in neuronal differentiation and spinogenesis in the FXS mouse model, taking the newly-produced OB neurons as a model;
3. To better characterize structural and functional presynaptic mechanisms in CA3 in the FXS mouse model and their link with the elevated expression of PDE2A and APC;
4. To define the molecular pathology underpinning FXS phenotypes characterized in aims 1, 2 and 3, and to unravel the impact of the modulation of PDE2A and APC levels on these pathways;
5. To decipher how FMRP regulates the translation and transport of PDE2A and APC mRNAs in in vitro and ex vivo systems at the single molecule level.
NotifX is based on a wealth of strong preliminary data and brings together the complementary and solid backgrounds of consortium members that will ensure the feasibility of this proposal.