Protein isoform processing, intracellular trafficking and cell vesicular bodies

• Grant number: 23/14788-0
• Support Opportunities: Regular Research Grants
• Start date: February 01, 2024
• End date: April 30, 2026
• Field of knowledge: Biological Sciences - Morphology - Cytology and Cell Biology
• Mobility Program: SPRINT - Projetos de pesquisa - Mobilidade
• Principal Investigator: Luciana Amaral Haddad
• Grantee: Luciana Amaral Haddad
• Principal researcher abroad: Barbara Bardoni
• Institution abroad: Centre National de la Recherche Scientifique, France
• Principal researcher abroad: Barbara Bardoni
• Institution abroad: Centre National de la Recherche Scientifique, France
• Host Institution: Instituto de Biociências (IB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 22/07948-9 - Molecular regulation of FMR1 variable transcripts and protein isoforms, AP.R

Abstract

Loss of function of fragile messenger ribonucleoprotein (FMRP), encoded by the FMR1 gene, leads to fragile X syndrome, the commonest inherited cause of intellectual disability among men. FMRP is an RNA-binding protein, mostly found in ribosomes and stress granules, with well-established roles in mRNA translation regulation in neurogenesis and synaptogenesis. FMRP is expressed as a group of protein isoforms due to alternative splicing of FMR1 primary transcript. Limited information is available at the protein level on the actual diversity of endogenous FMRP isoforms in the central nervous system. It is either known if regulated proteolysis can produce stable and functional FMRP isoforms. Research developed at the University of São Paulo shows that FMRP isoforms that express FMR1 alternative exon 12 as in-frame extension of one FMRP RNA-binding domain are significant in the rat brain and may associate with the biological membrane. Mass spectrometry analysis retrieved a protein network in association with these FMRP isoforms, with a specific subset of interactors enriched in the secretory/endolysosomal pathway. Collaborative research has been established between the University of São Paulo and Centre Nationale de Recherche Scientifique (CNRS, France) aiming at dissecting specific FMRP interactions with cofractionating proteins in a neuronal cell line and assessing the dependence of the association on RNA binding. Here, we propose the initial approach for this study as a SPRINT-funded researcher exchange between Brazil and France, comprehending a six-month sabbatical research work in France and lectures by each investigator in the academic setting of the foreign country. (AU)