Rescue of postnatal brain development in Coffin-Lowry Syndrome – RSK-ue

Coffin-Lowry syndrome (CLS) is a rare genetic disorder characterized by intellectual disability. To date, there is no preventive or curative treatment for this syndrome. CLS is caused by mutations in the Rsk2 gene, which encodes the RSK2 protein kinase. RSK2 acts at the end of the ERK/MAPK signaling pathway and also regulates this pathway via negative feedback. In our team, we have begun to characterize the role of RSK2 in brain development during the postnatal period. Using a mouse model of SCL (Rsk2-KO mice), we have demonstrated transient secondary microcephaly, appearing as early as 14 days of age (P14), associated with cellular defects in hippocampal and cerebellar development. We also identified a transient delay in sensorimotor development and cognitive alterations. Our results also revealed that the absence of RSK2 leads to over-activation of the ERK/MAPK pathway as early as P14. Thus, the absence of RSK2 alters the timing of certain developmental processes, which could explain the delayed brain development and associated cognitive deficits. In this project, we will deepen the identification of altered cellular and molecular mechanisms in the hippocampus and cerebellum in mouse CLS model during the postnatal period. From a translational point of view, we will develop and study cerebral organoid models carrying specific mutations of Rsk2 (non-sense and false sense mutations) and which in patients, lead to an alteration of the kinase activity of RSK2, or the loss of RSK2. This approach will allow us to determine the cellular and molecular alterations related to these types of mutations, which take place during brain development. Finally, in the CLS mouse model, we will assess, for the first time, a therapeutic approach administered as early as possible in the postnatal period, to rescue ERK over-activation. Based on the literature on therapeutic strategies used in RASopathies, we will use inhibitors known to down-regulate P-ERK during the early postnatal period. As a complementary therapeutic strategy, we will also assess whether the exposure of CLS mouse model to enriched environmental conditions, allow to correct the development and function of the hippocampus and cerebellum and, consequently, to prevent or to compensate for the emergence of sensory-motor, behavioral and cognitive deficits. In parallel, we will evaluate the translational potential of our pharmaceutical approach using our organoid models.