Rett syndrome and neurodevelopmental disorders
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 and neurodevelopmental diseases 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.
Within the Unit, a indipendent project headed by Patrizia d'Adamo is focused on the genetics of intellectual disabilities.
Gandaglia A, Brivio E, Carli S, Palmieri M, Bedogni F, Stefanelli G, Bergo A, Leva B, Cattaneo C, Pizzamiglio L, Cicerone M, Bianchi V, Kilstrup- Nielsen C, D'Annessa I, Di Marino D, D'Adamo P, Antonucci F, Frasca A, Landsberger N. A Novel Mecp2Y120D Knock-in Model Displays Similar Behavioral Traits But Distinct Molecular Features Compared to the Mecp2-Null Mouse Implying Precision Medicine for the Treatment of Rett Syndrome. Mol Neurobiol. 2018 Nov 6.
D'Annessa I, Gandaglia A, Brivio E, Stefanelli G, Frasca A, Landsberger N, Di Marino D. Tyr120Asp mutation alters domain exibility and dynamics of MeCP2 DNA binding domain leading to impaired DNA interaction: Atomistic characterization of a Rett syndrome causing mutation. Biochim Biophys Acta Gen Subj. 2018 May;1862(5):1180-1189.
Cobolli Gigli C, Scaramuzza L, De Simone M, Rossi RL, Pozzi D, Pagani M, Landsberger N, Bedogni F. Lack of Methyl-CpG Binding Protein 2 (MeCP2) Affects Cell Fate Refinement During Embryonic Cortical Development. Cereb Cortex. 2018 Jan 17.
Good KV, Martínez de Paz A, Tyagi M, Cheema MS, Thambirajah AA, Gretzinger TL, Stefanelli G, Chow RL, Krupke O, Hendzel M, Missiaen K, Underhill A, Landsberger N, Ausió J. Trichostatin A decreases the levels of MeCP2 expression and phosphorylation and increases its chromatin binding affinity. Epigenetics. 2017;12(11):934-944.
Stefanelli G, Gandaglia A, Costa M, Cheema MS, Di Marino D, Barbiero I, Kilstrup-Nielsen C, Ausió J, Landsberger N. Brain phosphorylation of MeCP2 at serine 164 is developmentally regulated and globally alters its chromatin association. Sci Rep. 2016; 6:28295.
Bedogni F, Cobolli Gigli C, Pozzi D, Rossi RL, Scaramuzza L, Rossetti G, Pagani M, Kilstrup- Nielsen C, Matteoli M, Landsberger N. Defects during Mecp2 null embryonic cortex development precede the onset of overt neurological symptoms. Cereb Cortex. 2016 Jun;26(6):2517-2529.
Conti V, Gandaglia A, Galli F, Tirone M, Bellini E, Campana L, Kilstrup-Nielsen C, Rovere- Querini P, Brunelli S, Landsberger N. MeCP2 affects skeletal muscle growth and morphology through non cell-autonomous mechanisms. PLoS One. 2015 Jun 22;10(6):e0130183.
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.
Bergo A, Strollo M, Gai M, Barbiero I, Stefanelli G, Sertic S, Cobolli Gigli C, Di Cunto F, Kilstrup-Nielsen C, Landsberger N. Methyl-CpG binding protein 2 (MeCP2) localizes at the centrosome and is required for proper mitotic spindle organization. J Biol Chem. 2015 Feb 6;290(6):3223-37.
Rusconi F, Paganini L, Braida D, Ponzoni L, Toffolo E, Maroli A, Landsberger N, Bedogni F, Turco E, Pattini L, Altruda F, De Biasi S, Sala M, Battaglioli E. LSD1 neurospecific alternative splicing controls neuronal excitability in mouse models of epilepsy. Cereb Cortex. 2015 Sep;25(9):2729-40.
Bellini E, Pavesi G, Barbiero I, Bergo A, Chandola C, Nawaz MS, Rusconi L, Stefanelli G, Strollo M, Valente MM, Kilstrup-Nielsen C, Landsberger N. MeCP2 post-translational modifications: a mechanism to control its involvement in synaptic plasticity and homeostasis? Front Cell Neurosci. 2014 Aug 13;8:236.
Bedogni F, Rossi RL, Galli F, Cobolli Gigli C, Gandaglia A, Kilstrup-Nielsen C, Landsberger N. Rett syndrome and the urge of novel approaches to study MeCP2 functions and mechanisms of action. Neurosci Biobehav Rev. Pt 2014 Oct;46 Pt 2:187-201.