Mutations in MECP2 cause several neuropsychiatric disorders including Rett syndrome (RTT) that represents the most common genetic cause of severe intellectual disability in girls. Although individually rare, together MECP2-opathies affect 1/4.000 individuals worldwide. Most of pathogenic MECP2 mutations are believed to cause loss-of- function of the protein. However, the existence of an MECP2 duplication syndrome suggests that gene replacement therapy might not represent a valid future therapeutic approach. Since MECP2 encodes a multifunctional protein with several roles in the regulation of gene expression, RTT is generally believed to be generated by perturbations in gene transcription. However, very few genes/pathways have been consistently linked to a dysfunctional MeCP2. No treatment is available to cure RTT. It has, however, been established that phenotypic rescue is possible in Mecp2-deficient mice upon reactivation of the endogenous Mecp2 gene, therefore raising the hope a possible cure.
Rett Research Unit aims to respond to the clinical need to develop rationally-designed suite of therapeutic measures or to identify robust biomarkers useful for preclinical studies.
- Identify which defects characterize MeCP2-null developing cortex. These studies are stem from a recently performed exhaustive analysis of the transcriptional defects displayed by the murine embryonic Mecp2-null neocortex, demonstrating a reduced responsiveness to external stimuli that persists in the perinatal age. Since activity is a major driver of neuronal maturation, we speculate part of the phenotypes affecting Mecp2 null animals derive from delayed maturation. To test this hypothesis, the unit will rescue maturation by enhancing neuronal activity through DREADD, a modified M3-muscarinic receptor designed to induce intracellular activity and Ca 2+ release through the modulation of G q protein. No longer sensitive to acetylcholine, DREADD can be selectively activated upon administration of Clozapine-N- Oxide (CNO), a molecule that is otherwise inert. A time course of the effects produced by enhancing intracellular activity through CNO chronic injection at different time points will enable to test our hypothesis.
- Characterize at the molecular level a novel phosphodefective KI mouse line reproducing a pathogenic human mutation.
- Search in the Mecp2 deficient mouse brain for novel deregulated molecular pathways with a therapeutic potential.
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La Montanara P, Rusconi L, Locarno A, Forti L, Barbiero I, Tramarin M, Chandola C, Kilstrup- Nielsen C, Landsberger N. Synaptic synthesis, dephosphorylation, and degradation: a novel paradigm for an activity-dependent neuronal control of CDKL5. J Biol Chem. 2015 Feb 13;290(7):4512-27.
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