FUNCTIONAL, BEHAVIORAL AND GENETIC STUDY TO UNDERSTAND THE PATHOGENETIC ROLE OF RAB AND RAB-ASSOCIATED PROTEINS IN HUMAN MENTAL RETARDATION

Human Mental Retardation (MR) is a common and highly heterogeneous paediatric disorder with a frequency of 2 to 3%, with a very severe social impact. Family studies have identified 215 X-linked different MR conditions, but only 82 mutated genes have been found until now. These genes encode for several proteins with a variety of functions: chromatin remodelling, pre/post synaptic activity, intracellular trafficking, etc.; and the general idea is that MR phenotype could emerge as abnormal cellular processing leading to pre- and/or post-synaptic neuronal terminals dysfunction. In our laboratory, we identified loss of function mutations in GDI1 and RAB39B genes that cause MR. Our research will focus on the identification of the molecular pathways altered in the absence of GDI1 and RAB39B genes. It is known that alphaGDI controls the activity of RAB proteins involved in intracellular trafficking, one of the pathways important for development of cognitive functions. The availability of a well-characterized Gdi1 KO mouse model for MR, that shows a defect in the regulation of these molecules, offers interesting perspectives for better defining their role in the brain. The proposed programme encompasses a large variety of techniques, spanning from genomic and proteomic approaches in combination with molecular biology and behavioural studies and the data generated, will carry out new insights in neuronal cell biology and development. Moreover, investigation of the neurobiological mechanisms underlying MR is a prerequisite for the development of therapies for the affected population