Molecular and cellular biology applied to neurodevelopmental disorders
Laboratory of molecular and cellular biology applied to neurodevelopmental disorders
The laboratory's research is focused on the study of pathologies associated with MECP2 and CDKL5 with a basic and translational approach. In general, all the basic projects developed aim to identify molecular and cellular defects that can serve to detect: i) biomarkers useful for studying disease progression and/or the efficacy of new therapeutic approaches; ii) defects that can become a logical target for new pre-clinical studies.
• We recently demonstrated how MeCP2 deficiency alters the formation of primary cilium and its functionality in vivo, in vitro and in patients’ cells. The primary cilium is a non-motile organelle, formed by microtubules, which projects from the surface of many cells, including neurons, playing the role of sensor of the extracellular environment and intercellular communication. The alteration of the cilium characterizes a set of pathologies called "ciliopathies", associated with developmental delay, mental disability, obesity and blindness. The ciliary defect found in cells without MeCP2 is reflected in a coherent and evident alteration of the Sonic Hedgehog (SHH) pathway, certainly essential for the development of the cerebellum. We also demonstrated how the inhibition of the HDAC6 enzyme represents an interesting approach to recover the morphological and functional phenotype of the primary cilium.
The logical extension of these recently published studies leads us mainly to:
a) describe in detail the morphological, molecular and cellular defects that characterize the development of a cerebellum free of Mecp2 and the adult cerebellum;
b) develop a new preclinical study aimed at evaluating the benefits of new pharmacological approaches aimed at restoring ciliary functions in mouse models of Rett syndrome.
• Several recent publications testify that Rett syndrome is not a purely neuronal pathology; in fact, astrocytes appear to have a relevant contribution. Nonetheless, the mechanisms by which astrocytes devoid of Mecp2 do not allow a correct maturation of wild type neurons remain unknown. Similarly, it is not yet clear which phenotypes distinguish Mecp2-defective astrocytes in vivo. In order to identify new therapeutic targets for Rett syndrome, a complex project of cellular and molecular biology is underway which, through imaging approaches and large-scale molecular analyses, will allow us to detect the astrocytic pathology that distinguishes the mouse models of Rett syndrome and its progression during disease progression.
• Many laboratories are involved in developing gene therapy approaches for the treatment of Rett syndrome and related disorders. In the laboratory, we decided to test the effectiveness of a different advanced therapy approach, based on cell transplantation. The study that has already led to interesting preliminary results is developed in vitro and in vivo and aims to understand the real benefit of the treatment and to identify the involved molecular mechanisms.
• Research proved that RTT is reversible at least in mice, but no cure is yet available: finding effective treatments represents a real social emergency. Several mouse models of Mecp2 are available which well reproduce the clinical features of Rett patients. These in vivo models often define the paradigm for research on the disease and drug discovery. On the other hand, compared to mouse, in vitro models offer the opportunity to carry out large-scale, rapid and relatively inexpensive drug screening systems, thus representing a valid first step of choice to be taken to select drugs for subsequent in vivo testing. Neurons differentiated from neural stem cells (NSCs) have recently gained much promise as powerful system for modelling a pathological condition and could provide a suitable source of cells for a drug screening system. We have recently optimized and characterized a neuronal model derived from mouse Mecp2 null NSCs showing that well-models RTT. The main objective of this project is to develop in vitro a new drug screening system for the treatment of Rett syndrome that is rapid, convenient, versatile and innovative. This system will combine the use of mouse neurons derived from NSC with microfluidic platforms useful for studying the recovery of gene expression.
Lab members: Nicoletta Landsberger (full professor of molecular biology); Angelisa Frasca (PostDoc); Eleonora Spiombi (PostDoc); Elena Albizzati (PhD fellow); Federica Miramondi (PhD fellow)
Contacts: firstname.lastname@example.org - tel:+39 02 50330464
Address: L.I.T.A Via Fratelli Cervi 93, 20090 Segrate, MI