Thesis defense Wallid Deb

The ubiquitin-proteasome system is a major actor of intracellular protein degradation in eukaryotes. Its involvement in neurodevelopmental disorders is ascertained, and more recently, proteasome subunits have been associated with syndromic intellectual disabilities. In this work, we set out to explore the existence of mechanisms common to this group of pathologies, as well as specific biomarkers for three candidate genes: PSMD11, CUL4B and USP7. Using blood samples, we amplified patients' T cells, on which we explored proteasome function and structure, as well as various molecular pathways of interest. Our results validate the relevance of biological markers associated with neurodevelopmental proteasomopathies, and the involvement of PSMD11 in the development of a NDD. The results regarding CUL4B and USP7 genes did not reveal any major deregulation. However, the results of omics explorations on T cells show abnormal expression patterns, which need to be explored and validated on neuronal models derived from patients, currently in progress. The ubiquitin-proteasome system appears to be a major actor of neurodevelopment, in which exploration in patient-derived cells is enabling us to refine our knowledge of its dysfunction.​