CELLULAR AND MOLECULAR STUDIES OF SYNAPTIC PLASTICITY AND CANCER IN THE CONTEXT OF INTELLECTUAL DISABILITIES. Memory formation and cognitive processes that rely on activity-dependent synaptic plasticity are affected by local protein synthesis and shaping of the synapses. Synaptic inputs dictate the time, place and amount of protein synthesis necessary for the single synapses. Dysregulation of these mechanisms leads to spine dysmorphogenesis and to a variety of neuropathological conditions including the most common form of inherited mental retardation, the Fragile X syndrome (FXS), which is due to the absence or mutation of a single protein, FMRP. FMRP is involved in multiple steps of neuronal messenger RNA metabolism such as transport, stability and local. Our work, as well as the work of others, has shown that Autistic Spectrum Disorder (ASD), Schizophrenia (SCZ) as well as Alzheimer’s Disease (AD) are linked to FMRP function.
We aim at identifying molecular pathways that are impaired in FXS and other disabilities such as ASD and SCZ using mouse and fly models as well as cell lines from patients. One of our major goals is to understand the regulation of synaptic protein synthesis and actin remodeling during brain development in physiological and the above-mentioned pathological conditions. We believe that the knowledge we acquire examining molecular mechanisms at the synapses will offer a major inroad into the understanding of processes that govern not only learning and memory, but also human behavior and neurodegenerative diseases that arise from malfunctioning synapses “synaptopathies”. Ultimately we aim, with the use of different mouse and fly models, stem cells and in collaboration with clinical researchers, to develop possible pharmacological approaches to modulate some aspects of FXS, ASD and SCZ.
A few clinical reports showed a decreased risk of cancer and neuroprotection in individuals with Fragile X. We have recently showed that FMRP levels correlate with prognostic indicators of aggressive breast cancer and metastasis. We have also identified key molecules involved in epithelial to mesenchymal transition and metastases formation, which are targeted at the mRNA level by FMRP. We are currently working on the molecular mechanisms conserved between cancer progression and neuronal development and exploring the possibility to identify potential therapeutic targets hindering metastasis dissemination.
Dysregulated ADAM10-Mediated Processing of APP during a Critical Time Window Leads to Synaptic Deficits in Fragile X SyndromePasciuto E, Ahmed T, Wahle T, Gardoni F, D'andrea L, Pacini L, Jacquemont S, Tassone F, Balschun D, Dotti C, Callaerts-Vegh Z, D'hooge R, Müller U, Di Luca M, De Strooper B, Bagni CNEURON, 87, 382-98, 2015 The Fragile X Protein binds mRNAs involved in cancer progression and modulates metastasis formationLucà R, Averna M, Zalfa F, Vecchi M, Bianchi F, La Fata G, Del Nonno F, Nardacci R, Bianchi M, Nuciforo P, Munck S, Parrella P, Moura R, Signori E, Alston R, Kuchnio A, Farace M, Fazio V, Piacentini M, De Strooper B, Achsel T, Neri G, Neven P, Evans D, Carmeliet P, Mazzone M, Bagni CEMBO Molecular Medicine, 5, 1523-1536, 2013
16/07/2015 - The discovery that it might also contribute to FXS, a neurodevelopmental disorder occurring at a young age, is remarkable.
17/11/2014 - Crucial role for FMRP (Fragile X Mental Retardation Protein) in embryonic development of the brain cortex
18/09/2013 - Several psychiatric conditions share the same brain cell abnormalities. Claudia Bagni and her group have unraveled how a single protein orchestrates two biological processes to form proper contacts between brain cells.
18/09/2013 - Claudia Bagni (VIB/KU Leuven, Belgium, and the University of Rome Tor Vergata, Italy), has identified the way Fragile X Mental Retardation Protein or FMRP contributes to the progression of breast cancer.