Mechanisms and therapeutic targets of NEDAMSS, a novel regressive neurodevelopmental syndrome

This project has been funded thanks to the Joint Call Fondazione Cariplo and Fondazione Telethon 2022 

The genetic basis of >1700 rare neurological disorders is still unclear and the function of many of the genes related to these disorders is not well characterized, which hampers the development of specific therapies. In the spirit of the Cariplo-Telethon Alliance call, this project aims to reduce this knowledge gap by focusing on NEDAMSS a rare, regressive neurodevelopmental disorder characterized by motor impairment, speech loss, and seizures, to define its molecular mechanisms and identify therapeutic targets. The disease is caused by mutations in a gene encoding the IRF2BPL protein, whose structure, function, and regulation are still not well characterized. Moreover, the mechanisms by which mutations in this gene cause disease are still unclear. This research, through a combination of multiple molecular and cellular approaches, including the use of human neurons carrying NEDAMSS mutations derived from stem cells, has two main aims. First, it aims at clarifying the structure and function of the IRF2BPL protein, identifying regulatory mechanisms of its function related to a process called SUMOylation, which may represent a promising pharmacological target for NEDAMSS. Second, it aims at defining the effects of NEDAMSS-related mutations on the structure and function of the protein, and how SUMOylation-regulating drugs may limit these negative effects. Overall, the results of this research will illuminate the molecular mechanisms underlying IRF2BPL-related NEDAMSS, with the potential to identify novel therapeutic targets and drugs for NEDAMSS, a disease that currently has no effective treatment.