Verslag – Rapport – Bericht – Report - GSKE - FMRE

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Principal investigator: Prof. Claudia Bagni Faculty of Medicine. Developmental and Molecular Genetics Section (VIB11) Catholic University of Leuven, Belgium e-mail: claudia.bagni@med.kuleuven.be Tel: +32-16330944 Fax: +32-16330939 18 Verslag – Rapport – Report 2012
mRNA metabolism at synapses and spine remodeling: insights into Fragile X, Autism and Schizophrenia A STATE OF THE ART AND SUMMARY OF THE RESEARCH PROGRAM Memory formation and cognitive processes rely on activity-dependent synaptic plasticity. Synaptic inputs dictate the time, place and amount of protein synthesis necessary for the single synapses. Dysregulation of these mechanisms leads to spine dysmorphogenesis (Fiala et al., 2002) and to a variety of pathological conditions including the most common form of inherited mental retardation due to the absence or mutation of a single protein, FMRP (Bagni et al., 2012). FMRP is involved in multiple steps of neuronal messenger RNA metabolism such as transport, stability and local translation. We have shown that FMRP, together with its cytoplasmic interactor CYFIP1, controls, in an activity dependent manner, the synthesis of key proteins at synapses, which are impaired in a mouse model for FXS. The protein CYFIP1 has a critical role in human brain function/s. Deletions and/or duplications of CYFIP1 have been associated to Autism, Schizophrenia and Epilepsy (Bittel et al., 2006; Chai et al., 2003; Doornbos et al., 2009; Tam et al., 2010; van der Zwaag et al., 2010; von der Lippe et al., 2010). Using a mouse model (Cyfip1 KO) and other model systems (Bozdagi et al., 2012; Schenck et al., 2003; Star et al., 2002) it has been shown that CYFIP1 is involved in the formation of synaptic processes. Therefore unbalances in CYFIP1 interactive network/s might result in neuronal dysfunctions as dendritic spines dysgenesis: a common cellular phenotype observed in patients with Fragile X Syndrome and other mental disorders (Fiala et al., 2002). In the proposed project we plan to: 1) Identify and characterize the CYFIP1 complexes in different neuronal compartments, 2) Investigate whether the Rho GTPase Rac1, a CYFIP1 interactor, regulates CYFIP1-dependent protein synthesis, 3) Study the physiological regulation of FMRP and CYFIP1 upon synaptic activation. This project will shed light into mental retardation, Autism and possibly schizophrenia. B RESULTS To understand the role of CYFIP1 in all these complex diseases, we have identified CYFIP1 synaptic complexes and characterized its neuronal functions through the following aims: Aim 1: Identification and characterization of the CYFIP1 complexes in different neuronal compartments, i.e. cortex, hippocampus and isolated synapses. Achievement 1: To isolate the CYFIP1 complexes, we have immunoprecipitated CYFIP1 using a specific antibody (Napoli et al., 2008). The co-interacting proteins were then analyzed by liquid chromatography/mass spectrometry analysis (LC-MS/MS), in collaboration with the group of Prof. August B. Smit, Dept. of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, VU University Amsterdam, The Netherlands. We performed electron microscopic (EM), and immunohistochemistry (IHC) studies that indicate that CYFIP1 and FMRP are enriched at synapses. We next focused on this highly specialized subcellular compartment which, as previously mentioned, is largely affected in several neurological syndromes and in mental retardation (Fiala et al., 2002). At synapses, we identified 35 novel Verslag – Rapport – Report 2012 19
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