Final Activity Report Summary - FRAXA MRNP (Characterization and dynamics of ribonucleoprotein complexes containing the Fragile Mental Retardation Protein involved in the Fragile X Syndrome)
Mental retardation (MR) is a major cause of serious handicap and an important medical and social issue, affecting 1 to 1.5% of the population. The Fragile X Syndrome (FXS) is the most frequent hereditary cause of MR affecting 1/4000 males and 1/7000 females, due to the inactivation of the X-linked Fragile X Mental Retardation 1 gene (FMR1). In FXS patients and the Fmr1 knock-out mouse, the lack of the gene product, the RNA-binding protein FMRP, induces behavioural and cognitive abnormalities, coupled to alterations of synaptic plasticity and morphology, most probably due to alterations of the transport and localised synaptic translation of specific mRNA targets of FMRP. We believe that FMRP's functions strongly depend on RNA and/or proteins that interact and associate with it, therefore I proposed to characterize the mRNP complexes containing FMRP, at the level of mRNA and protein composition.
First, I have developed in collaboration with my previous post-doc laboratory (Prof. Khandjian, Québec, Canada) a biochemical method to purify RNA granules from mouse brain, an RNP structure involved in the transport of mRNA in the neuronal arborisation. I will now be able to use this method to obtain substantial amounts of mRNA granules necessary to characterise novel mRNA targets of FMRP specific to these structures.
Second, I have contributed to the characterisation of a novel mRNA recognition sequences and/or structures bound by FMRP, the SoSLIP triple stem loop structure present on SOD1 mRNA involved in translation activation via FMRP.
Finally, I have participated to the investigation of the role of well-known proteins interacting with FMRP, the isoforms of its close homologue FXR1P, in the modulation of its interaction with the G-quartet mRNA structure.
This project was developed in Dr Bardoni's laboratory but also partly in close collaboration with a Canadian laboratory (Prof. Khandjian, Univ. Laval, Québec) and has contributed significantly to the understanding of the neuronal alterations induced by the absence of FMRP in FXS patients.
I will continue to develop the study of FMRP in the context of its RNP complexes in brain, in particular in dendritic RNA granules. I recently got a permanent position as a research associate at the CNRS (start Feb 2010) in Dr Bardoni's laboratory in order to pursue the development of this research program, for which I recently received two starting grants: ERG Marie Curie Grant and FRAXA research foundation Grant.
First, I have developed in collaboration with my previous post-doc laboratory (Prof. Khandjian, Québec, Canada) a biochemical method to purify RNA granules from mouse brain, an RNP structure involved in the transport of mRNA in the neuronal arborisation. I will now be able to use this method to obtain substantial amounts of mRNA granules necessary to characterise novel mRNA targets of FMRP specific to these structures.
Second, I have contributed to the characterisation of a novel mRNA recognition sequences and/or structures bound by FMRP, the SoSLIP triple stem loop structure present on SOD1 mRNA involved in translation activation via FMRP.
Finally, I have participated to the investigation of the role of well-known proteins interacting with FMRP, the isoforms of its close homologue FXR1P, in the modulation of its interaction with the G-quartet mRNA structure.
This project was developed in Dr Bardoni's laboratory but also partly in close collaboration with a Canadian laboratory (Prof. Khandjian, Univ. Laval, Québec) and has contributed significantly to the understanding of the neuronal alterations induced by the absence of FMRP in FXS patients.
I will continue to develop the study of FMRP in the context of its RNP complexes in brain, in particular in dendritic RNA granules. I recently got a permanent position as a research associate at the CNRS (start Feb 2010) in Dr Bardoni's laboratory in order to pursue the development of this research program, for which I recently received two starting grants: ERG Marie Curie Grant and FRAXA research foundation Grant.